Publications by authors named "Richard Green"

502 Publications

Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1.

PLoS One 2022 14;17(1):e0261789. Epub 2022 Jan 14.

Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261789PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759640PMC
January 2022

HRD1-mediated METTL14 degradation regulates mA mRNA modification to suppress ER proteotoxic liver disease.

Mol Cell 2021 Dec 29;81(24):5052-5065.e6. Epub 2021 Nov 29.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers an unfolded protein response (UPR) for stress adaptation, the failure of which induces cell apoptosis and tissue/organ damage. The molecular switches underlying how the UPR selects for stress adaptation over apoptosis remain unknown. Here, we discovered that accumulation of unfolded/misfolded proteins selectively induces N-adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes C/EBP-homologous protein (CHOP) mRNA decay through its 3' UTR N-methyladenosine (mA) to inhibit its downstream pro-apoptotic target gene expression. UPR induces METTL14 expression by competing against the HRD1-ER-associated degradation (ERAD) machinery to block METTL14 ubiquitination and degradation. Therefore, mice with liver-specific METTL14 deletion are highly susceptible to both acute pharmacological and alpha-1 antitrypsin (AAT) deficiency-induced ER proteotoxic stress and liver injury. Further hepatic CHOP deletion protects METTL14 knockout mice from ER-stress-induced liver damage. Our study reveals a crosstalk between ER stress and mRNA mA modification pathways, termed the ERmA pathway, for ER stress adaptation to proteotoxicity.
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http://dx.doi.org/10.1016/j.molcel.2021.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751812PMC
December 2021

Hereditary haemorrhagic telangiectasia: development of a regional life-course collaborative clinical care pathway.

Br J Hosp Med (Lond) 2021 Nov 23;82(11):1-9. Epub 2021 Nov 23.

Department of Paediatric Respiratory Medicine, Alder Hey Children's Hospital, Liverpool, UK.

Hereditary haemorrhagic telangiectasia is a rare, genetic disorder that can present at any age. It is characterised by epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations, which can affect multiple organs. Early diagnosis and management reduces the morbidity and mortality associated with the disease. There is a well-established hereditary haemorrhagic telangiectasia clinic in London, and excellent links across Europe via the European Reference Network. However, local coordinated care for patients with hereditary haemorrhagic telangiectasia across the UK can be variable and often absent for children and young people. Some patients travel long distances to receive care in London, while others are referred to local clinicians or lost to follow up entirely. This article presents the experience to date from two regional UK centres (Liverpool and Dundee) where care for patients with hereditary haemorrhagic telangiectasia is being coordinated and streamlined. While there is still a lot to learn, this article highlights some of the successes and challenges identified so far, with suggestions for how these could be addressed. Collaborative regional networks such as these can facilitate the sharing of best practice and ensure that all patients with hereditary haemorrhagic telangiectasia are able to access safe, high-quality care.
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http://dx.doi.org/10.12968/hmed.2020.0537DOI Listing
November 2021

Hereditary haemorrhagic telangiectasia: an overview from an ear, nose and throat perspective.

Br J Hosp Med (Lond) 2021 Nov 23;82(11):1-9. Epub 2021 Nov 23.

Liverpool Head and Neck Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.

Patients with hereditary haemorrhagic telangiectasia can present with a multitude of symptoms caused by telangiectasia and arteriovenous malformations in the nose, brain, gastrointestinal tract, liver and spinal cord. Clinicians should be aware of the potential diagnosis of hereditary haemorrhagic telangiectasia and how to manage these patients both in the acute and chronic setting. Identifying these patients and optimising their management can help reverse the reduced life expectancy back to that of the normal population. The management of these patients is complex and often requires a multidisciplinary approach, with difficult discussions to be had around screening for arteriovenous malformations and genetic testing. The stepwise management ladder can be used in both the medical and surgical strategies; there are multiple pharmacological and surgical options available, all with their own side effects and risks. Patient education is key to help informed decision making. This article outlines the clinical characteristics of the disease and management options available.
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http://dx.doi.org/10.12968/hmed.2020.0560DOI Listing
November 2021

AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models.

Nucleic Acids Res 2022 Jan;50(D1):D439-D444

European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK.

The AlphaFold Protein Structure Database (AlphaFold DB, https://alphafold.ebi.ac.uk) is an openly accessible, extensive database of high-accuracy protein-structure predictions. Powered by AlphaFold v2.0 of DeepMind, it has enabled an unprecedented expansion of the structural coverage of the known protein-sequence space. AlphaFold DB provides programmatic access to and interactive visualization of predicted atomic coordinates, per-residue and pairwise model-confidence estimates and predicted aligned errors. The initial release of AlphaFold DB contains over 360,000 predicted structures across 21 model-organism proteomes, which will soon be expanded to cover most of the (over 100 million) representative sequences from the UniRef90 data set.
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http://dx.doi.org/10.1093/nar/gkab1061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728224PMC
January 2022

Systematic experimental comparison of particle filtration efficiency test methods for commercial respirators and face masks.

Sci Rep 2021 11 9;11(1):21979. Epub 2021 Nov 9.

Metrology Research Centre, National Research Council Canada, Ottawa, ON, K1A 0R6, Canada.

Respirators, medical masks, and barrier face coverings all filter airborne particles using similar physical principles. However, they are tested for certification using a variety of standardized test methods, creating challenges for the comparison of differently certified products. We have performed systematic experiments to quantify and understand the differences between standardized test methods for N95 respirators (NIOSH TEB-APR-STP-0059 under US 42 CFR 84), medical face masks (ASTM F2299/F2100), and COVID-19-related barrier face coverings (ASTM F3502-21). Our experiments demonstrate the role of face velocity, particle properties (mean size, size variability, electric charge, density, and shape), measurement techniques, and environmental preconditioning. The measured filtration efficiency was most sensitive to changes in face velocity and particle charge. Relative to the NIOSH method, users of the ASTM F2299/F2100 method have commonly used non-neutralized (highly charged) aerosols as well as smaller face velocities, each of which may result in approximately 10% higher measured filtration efficiencies. In the NIOSH method, environmental conditioning at elevated humidity increased filtration efficiency in some commercial samples while decreasing it in others, indicating that measurement should be performed both with and without conditioning. More generally, our results provide an experimental basis for the comparison of respirators certified under various international methods, including FFP2, KN95, P2, Korea 1st Class, and DS2.
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http://dx.doi.org/10.1038/s41598-021-01265-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578374PMC
November 2021

Patient-Reported Outcomes in Middle Ear and Active Transcutaneous Bone Conduction Hearing Implants.

J Int Adv Otol 2021 Sep;17(5):405-411

Department of Otolaryngology, Ninewells Hospital and Medical School, Ninewells Avenue, Dundee, United Kingdom.

Objective: This study used questionnaires to examine the patient-reported satisfaction with 2 hearing implant devices to determine the level of overall satisfaction with the devices, which, if any, factors predicted good or poor perceived outcomes, or whether there were any specific aspects of the devices where dissatisfaction was apparent.

Methods: A post-treatment questionnaire survey of 39 adult patients who had received a Vibrant Soundbridge (VSB) or Bonebridge (BB) hearing implant, with at least 3 months of follow-up, was conducted using the Glasgow Benefit Inventory (GBI) and Hearing Device Satisfaction Scale (HDSS). Satisfaction scores were compared to pre- and post-operative audiologic outcomes. The correlation between GBI and HDSS scores was also examined.

Results: A total of 28 of the 39 patients (72%) responded: 13 with a BB and 15 with a VSB at a mean of 13 months after implantation. The overall mean total GBI score was 30, with no significant differences across the groups. The responders generally reported that they were "satisfied" across most domains of the HDSS. In the study, 25 of the 28 responders were largely satisfied with their devices but 3 respondents were not. Two were known non-users, while one used the device but did not gain the benefit expected. It is instructive to note that all of these dissatisfied recipients were close to the manufacturer recommended limits for implantation of their respective devices at the time of surgery. Certain themes were identified within the patients' responses, indicating common aspects where satisfaction was poorer.

Conclusion: This series of 28 implant recipients demonstrates high levels of satisfaction with implantable hearing devices across 2 different validated questionnaires. Implant teams could exercise caution and manage patient expectations if the patients are close to the recommended limits of a particular device.
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http://dx.doi.org/10.5152/iao.2021.21077DOI Listing
September 2021

Supernumerary tooth in nasopalatine canal: a rare cause of septal cartilage collapse.

BMJ Case Rep 2021 Sep 21;14(9). Epub 2021 Sep 21.

Department of ENT, Ninewells Hospital, Dundee, UK.

Mesiodens is the most common type of supernumerary tooth, located between the maxillary central incisors in close relation to the nasopalatine canal. A 20-year-old man presented with right-sided nasal blockage, nasal discharge and collapsed nose without history of trauma. Imaging revealed a calcified mass in the inferior meatus extending into dilated nasopalatine canal. Endoscopic removal of the mass revealed tuberculate appearance of an incompletely developed tooth, consistent with mesiodens. Based on the history of septal cartilage collapse with right-sided mucopurulent discharge, endoscopic findings of the right inferior turbinate being adherent to the septal cartilage and the underlying mesiodens, we believe that the patient developed a septal abscess secondary to infection in nasal mucosa surrounding the mesiodens causing collapse of septal cartilage. While a tooth or tooth-like mass causing nasal passage air-flow obstruction is uncommon, we believe that this is the first reported case of mesiodens presenting with septal cartilage collapse.
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http://dx.doi.org/10.1136/bcr-2021-245103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458351PMC
September 2021

A chromosome-scale genome assembly and karyotype of the ctenophore Hormiphora californensis.

G3 (Bethesda) 2021 10;11(11)

Department of Biomolecular Engineering and Bioinformatics, University of California Santa Cruz, Santa Cruz, CA 95064, USA.

Here, we present a karyotype, a chromosome-scale genome assembly, and a genome annotation from the ctenophore Hormiphora californensis (Ctenophora: Cydippida: Pleurobrachiidae). The assembly spans 110 Mb in 44 scaffolds and 99.47% of the bases are contained in 13 scaffolds. Chromosome micrographs and Hi-C heatmaps support a karyotype of 13 diploid chromosomes. Hi-C data reveal three large heterozygous inversions on chromosome 1, and one heterozygous inversion shares the same gene order found in the genome of the ctenophore Pleurobrachia bachei. We find evidence that H. californensis and P. bachei share thirteen homologous chromosomes, and the same karyotype of 1n = 13. The manually curated PacBio Iso-Seq-based genome annotation reveals complex gene structures, including nested genes and trans-spliced leader sequences. This chromosome-scale assembly is a useful resource for ctenophore biology and will aid future studies of metazoan evolution and phylogenetics.
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http://dx.doi.org/10.1093/g3journal/jkab302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527503PMC
October 2021

An ancestral recombination graph of human, Neanderthal, and Denisovan genomes.

Sci Adv 2021 Jul 16;7(29). Epub 2021 Jul 16.

Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.

Many humans carry genes from Neanderthals, a legacy of past admixture. Existing methods detect this archaic hominin ancestry within human genomes using patterns of linkage disequilibrium or direct comparison to Neanderthal genomes. Each of these methods is limited in sensitivity and scalability. We describe a new ancestral recombination graph inference algorithm that scales to large genome-wide datasets and demonstrate its accuracy on real and simulated data. We then generate a genome-wide ancestral recombination graph including human and archaic hominin genomes. From this, we generate a map within human genomes of archaic ancestry and of genomic regions not shared with archaic hominins either by admixture or incomplete lineage sorting. We find that only 1.5 to 7% of the modern human genome is uniquely human. We also find evidence of multiple bursts of adaptive changes specific to modern humans within the past 600,000 years involving genes related to brain development and function.
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http://dx.doi.org/10.1126/sciadv.abc0776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284891PMC
July 2021

Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy.

PLoS Pathog 2021 07 6;17(7):e1009278. Epub 2021 Jul 6.

Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.

Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge.
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http://dx.doi.org/10.1371/journal.ppat.1009278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284654PMC
July 2021

Hepatic X-Box Binding Protein 1 and Unfolded Protein Response Is Impaired in Weanling Mice With Resultant Hepatic Injury.

Hepatology 2021 12 9;74(6):3362-3375. Epub 2021 Sep 9.

Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Background And Aims: The unfolded protein response (UPR) is a coordinated cellular response to endoplasmic reticulum (ER) stress that functions to maintain cellular homeostasis. When ER stress is unresolved, the UPR can trigger apoptosis. Pathways within the UPR influence bile acid metabolism in adult animal models and adult human liver diseases, however, the UPR has not been studied in young animal models or pediatric liver diseases. In this study we sought to determine whether weanling age mice had altered UPR activation compared with adult mice, which could lead to increased bile acid-induced hepatic injury.

Approach And Results: We demonstrate that after 7 days of cholic acid (CA) feeding to wild-type animals, weanling age mice have a 2-fold greater serum alanine aminotransferase (ALT) levels compared with adult mice, with increased hepatic apoptosis. Weanling mice fed CA have increased hepatic nuclear X-box binding protein 1 spliced (XBP1s) expression, but cannot increase expression of its protective downstream target's ER DNA J domain-containing protein 4 and ER degradation enhancing α-mannoside. In response to tunicamycin induced ER stress, young mice have blunted expression of several UPR pathways compared with adult mice. CA feeding to adult liver-specific XBP1 knockout (LS-XBP1 ) mice, which are unable to resolve hepatic ER stress, leads to increased serum ALT and CCAAT/enhancer binding homologous protein, a proapoptotic UPR molecule, expression to levels similar to CA-fed LS-XBP1 weanlings.

Conclusions: Weanling mice have attenuated hepatic XBP1 signaling and impaired UPR activation with resultant increased susceptibility to bile acid-induced injury.
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http://dx.doi.org/10.1002/hep.32031DOI Listing
December 2021

Multimodal analysis for human studies shows extensive molecular changes from delays in blood processing.

iScience 2021 May 15;24(5):102404. Epub 2021 Apr 15.

Allen Institute for Immunology, Seattle, WA 98109, USA.

Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMC up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.
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http://dx.doi.org/10.1016/j.isci.2021.102404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169801PMC
May 2021

A case report. Tenosynovial giant cell tumour in the tendon of extensor digitorium longus.

Foot (Edinb) 2021 Jun 23;47:101775. Epub 2021 Jan 23.

Wye Valley NHS Trust, Department of Podiatric Surgery, Belmont, Ruckland Lane, Hereford, United Kingdom. Electronic address:

Soft tissue lesions found within the foot and ankle can vary in their origin. Tenosynovial giant-cell tumours (TSGCT) are quoted as rare in their presentation yet also reported to be the sixth most common benign lesion in the foot. This article presents a case report following the patient journey suffering with a TSGCT of the fourth toe. From initial consultation, to further investigation with advanced imaging to a final decision on surgical excision following consideration of conservative management.
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http://dx.doi.org/10.1016/j.foot.2021.101775DOI Listing
June 2021

Towards complete and error-free genome assemblies of all vertebrate species.

Nature 2021 04 28;592(7856):737-746. Epub 2021 Apr 28.

UQ Genomics, University of Queensland, Brisbane, Queensland, Australia.

High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species. To address this issue, the international Genome 10K (G10K) consortium has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences.
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http://dx.doi.org/10.1038/s41586-021-03451-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081667PMC
April 2021

Correlation of Regulatory T Cell Numbers with Disease Tolerance upon Virus Infection.

Immunohorizons 2021 04 23;5(4):157-169. Epub 2021 Apr 23.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA;

The goal of a successful immune response is to clear the pathogen while sparing host tissues from damage associated with pathogen replication and active immunity. Regulatory T cells (Treg) have been implicated in maintaining this balance as they contribute both to the organization of immune responses as well as restriction of inflammation and immune activation to limit immunopathology. To determine if Treg abundance prior to pathogen encounter can be used to predict the success of an antiviral immune response, we used genetically diverse mice from the collaborative cross infected with West Nile virus (WNV). We identified collaborative cross lines with extreme Treg abundance at steady state, either high or low, and used mice with these extreme phenotypes to demonstrate that baseline Treg quantity predicted the magnitude of the CD8 T cell response to WNV infection, although higher numbers of baseline Tregs were associated with reduced CD8 T cell functionality in terms of TNF and granzyme B expression. Finally, we found that abundance of CD44 Tregs in the spleen at steady state was correlated with an increased early viral load within the spleen without an association with clinical disease. Thus, we propose that Tregs participate in disease tolerance in the context of WNV infection by tuning an appropriately focused and balanced immune response to control the virus while at the same time minimizing immunopathology and clinical disease. We hypothesize that Tregs limit the antiviral CD8 T cell function to curb immunopathology at the expense of early viral control as an overall host survival strategy.
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http://dx.doi.org/10.4049/immunohorizons.2100009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281504PMC
April 2021

An Annotated Draft Genome for the Andean Bear, Tremarctos ornatus.

J Hered 2021 07;112(4):377-384

Department of Ecology and Evolutionary Biology, University of California Santa Cruz, Santa Cruz, CA.

The Andean bear is the only extant member of the Tremarctine subfamily and the only extant ursid species to inhabit South America. Here, we present an annotated de novo assembly of a nuclear genome from a captive-born female Andean bear, Mischief, generated using a combination of short and long DNA and RNA reads. Our final assembly has a length of 2.23 Gb, and a scaffold N50 of 21.12 Mb, contig N50 of 23.5 kb, and BUSCO score of 88%. The Andean bear genome will be a useful resource for exploring the complex phylogenetic history of extinct and extant bear species and for future population genetics studies of Andean bears.
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http://dx.doi.org/10.1093/jhered/esab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280923PMC
July 2021

Simultaneous trimodal single-cell measurement of transcripts, epitopes, and chromatin accessibility using TEA-seq.

Elife 2021 04 9;10. Epub 2021 Apr 9.

Allen Institute for Immunology, Seattle, United States.

Single-cell measurements of cellular characteristics have been instrumental in understanding the heterogeneous pathways that drive differentiation, cellular responses to signals, and human disease. Recent advances have allowed paired capture of protein abundance and transcriptomic state, but a lack of epigenetic information in these assays has left a missing link to gene regulation. Using the heterogeneous mixture of cells in human peripheral blood as a test case, we developed a novel scATAC-seq workflow that increases signal-to-noise and allows paired measurement of cell surface markers and chromatin accessibility: integrated cellular indexing of chromatin landscape and epitopes, called ICICLE-seq. We extended this approach using a droplet-based multiomics platform to develop a trimodal assay that simultaneously measures transcriptomics (scRNA-seq), epitopes, and chromatin accessibility (scATAC-seq) from thousands of single cells, which we term TEA-seq. Together, these multimodal single-cell assays provide a novel toolkit to identify type-specific gene regulation and expression grounded in phenotypically defined cell types.
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http://dx.doi.org/10.7554/eLife.63632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034981PMC
April 2021

A Novel Precision Approach to Overcome the "Addiction Pandemic" by Incorporating Genetic Addiction Risk Severity (GARS) and Dopamine Homeostasis Restoration.

J Pers Med 2021 Mar 16;11(3). Epub 2021 Mar 16.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.

This article describes a unique therapeutic precision intervention, a formulation of enkephalinase inhibitors, enkephalin, and dopamine-releasing neuronutrients, to induce dopamine homeostasis for detoxification and treatment of individuals genetically predisposed to developing reward deficiency syndrome (RDS). The formulations are based on the results of the addiction risk severity (GARS) test. Based on both neurogenetic and epigenetic evidence, the test evaluates the presence of reward genes and risk alleles. Existing evidence demonstrates that the novel genetic risk testing system can successfully stratify the potential for developing opioid use disorder (OUD) related risks or before initiating opioid analgesic therapy and RDS risk for people in recovery. In the case of opioid use disorders, long-term maintenance agonist treatments like methadone and buprenorphine may create RDS, or RDS may have been in existence, but not recognized. The test will also assess the potential for benefit from medication-assisted treatment with dopamine augmentation. RDS methodology holds a strong promise for reducing the burden of addictive disorders for individuals, their families, and society as a whole by guiding the restoration of dopamine homeostasisthrough anti-reward allostatic neuroadaptations. WC 175.
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http://dx.doi.org/10.3390/jpm11030212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002215PMC
March 2021

A Fast and Efficient Single-stranded Genomic Library Preparation Method Optimized for Ancient DNA.

J Hered 2021 05;112(3):241-249

Department of Ecology and Evolutionary Biology, University of California Santa Cruz, Santa Cruz, CA.

We present a protocol to prepare extracted DNA for sequencing on the Illumina sequencing platform that has been optimized for ancient and degraded DNA. Our approach, the Santa Cruz Reaction or SCR, uses directional splinted ligation of Illumina's P5 and P7 adapters to convert natively single-stranded DNA and heat denatured double-stranded DNA into sequencing libraries in a single enzymatic reaction. To demonstrate its efficacy in converting degraded DNA molecules, we prepare 5 ancient DNA extracts into sequencing libraries using the SCR and 2 of the most commonly used approaches for preparing degraded DNA for sequencing: BEST, which targets and converts double-stranded DNA, and ssDNA2.0, which targets and converts single-stranded DNA. We then compare the efficiency with which each approach recovers unique molecules, or library complexity, given a standard amount of DNA input. We find that the SCR consistently outperforms the BEST protocol in recovering unique molecules and, despite its relative simplicity to perform and low cost per library, has similar performance to ssDNA2.0 across a wide range of DNA inputs. The SCR is a cost- and time-efficient approach that minimizes the loss of unique molecules and makes accessible a taxonomically, geographically, and a temporally broader sample of preserved remains for genomic analysis.
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http://dx.doi.org/10.1093/jhered/esab012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141684PMC
May 2021

Should We Embrace the Incorporation of Genetically Guided "Dopamine Homeostasis" in the Treatment of Reward Deficiency Syndrome (RSD) as a Frontline Therapeutic Modality?

Acta Sci Neurol 2021 Feb;4(2):17-24

Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, San Antonio, TX, Long School of Medicine, University of Texas Medical Center, San Antonio, TX, USA.

In 2019, the US Center for Disease Control and Prevention provided vital statistics related to drug overdoses in the United State1. They concluded that in the USA the number of deaths at almost 72,000 was due to 66.6% of opioid overdoses. In fact, the rate is alarming and increasing yearly. To make 2021 even more scary is the daunting effect on increased drug usage due to COVID 19 as a pandemic, albeit the new vaccines. Specifically, in 2020, the death rate from opioid overdoses rose to 13% nationally and in some sates 30%. The common neuromodulating aspects of neurotransmission, and its disruption via chronic exposure of drugs and behavioral addictions, requires further intense research focus on developing novel strategies to combat these unwanted genetic and epigenic infractions as accomplished with heroin addiction by our group. The take home message is the plausible acceptance of the well-established evidence for hypodopaminergia, a blunted reward processing system, reduced resting state functional connectivity, genetic antecedents, anti- reward symptomatology, poor compliance with MAT, and generalized RDS. With this evidence it is conceivable that pursuit through intensive future research should involve an approach that incorporates "dopamine homeostasis". This required paradigm shift may consist of many beneficial modalities including but not limited to: exercise, pro-dopamine regulation, nutrigenomics, cognitive behavioral therapy, hedonic hot spot targets brain, rTMRS, deep brain stimulation, diet, genetic edits, genetic guided therapeutics, epigenetic repair, amongst others. It is our opinion that nutrigenomics may assist the millions of people of getting out of a" hypodopaminergic ditch" WC 250.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931265PMC
February 2021

A Reference Genome Assembly of American Bison, Bison bison bison.

J Hered 2021 03;112(2):174-183

USDA, ARS, U.S. Meat Animal Research Center, Clay Center, NE, USA.

Bison are an icon of the American West and an ecologically, commercially, and culturally important species. Despite numbering in the hundreds of thousands today, conservation concerns remain for the species, including the impact on genetic diversity of a severe bottleneck around the turn of the 20th century and genetic introgression from domestic cattle. Genetic diversity and admixture are best evaluated at genome-wide scale, for which a high-quality reference is necessary. Here, we use trio binning of long reads from a bison-Simmental cattle (Bos taurus taurus) male F1 hybrid to sequence and assemble the genome of the American plains bison (Bison bison bison). The male haplotype genome is chromosome-scale, with a total length of 2.65 Gb across 775 scaffolds (839 contigs) and a scaffold N50 of 87.8 Mb. Our bison genome is ~13× more contiguous overall and ~3400× more contiguous at the contig level than the current bison reference genome. The bison genome sequence presented here (ARS-UCSC_bison1.0) will enable new research into the evolutionary history of this iconic megafauna species and provide a new tool for the management of bison populations in federal and commercial herds.
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http://dx.doi.org/10.1093/jhered/esab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006816PMC
March 2021

Reintroduction of the archaic variant of in cortical organoids alters neurodevelopment.

Science 2021 02;371(6530)

Department of Pediatrics and Department of Cellular & Molecular Medicine, School of Medicine, Center for Academic Research and Training in Anthropogeny (CARTA), Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA 92037, USA.

The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 () plays a key role in neural development and function. also includes a protein-coding difference between the modern human genome and Neanderthal and Denisovan genomes. To investigate the functional importance of an amino acid change in humans, we reintroduced the archaic allele into human induced pluripotent cells using genome editing and then followed their neural development through cortical organoids. This modification promoted slower development and higher surface complexity in cortical organoids with the archaic version of Moreover, levels of synaptic markers and synaptic protein coassociations correlated with altered electrophysiological properties in organoids expressing the archaic variant. Our results suggest that the human-specific substitution in , which is exclusive to modern humans since divergence from Neanderthals, may have had functional consequences for our species' evolution.
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http://dx.doi.org/10.1126/science.aax2537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006534PMC
February 2021

A Reference Genome Assembly of Simmental Cattle, Bos taurus taurus.

J Hered 2021 03;112(2):184-191

USDA, ARS, Animal Genomics and Improvement Laboratory, Beltsville, MD.

Genomics research has relied principally on the establishment and curation of a reference genome for the species. However, it is increasingly recognized that a single reference genome cannot fully describe the extent of genetic variation within many widely distributed species. Pangenome representations are based on high-quality genome assemblies of multiple individuals and intended to represent the broadest possible diversity within a species. A Bovine Pangenome Consortium (BPC) has recently been established to begin assembling genomes from more than 600 recognized breeds of cattle, together with other related species to provide information on ancestral alleles and haplotypes. Previously reported de novo genome assemblies for Angus, Brahman, Hereford, and Highland breeds of cattle are part of the initial BPC effort. The present report describes a complete single haplotype assembly at chromosome-scale for a fullblood Simmental cow from an F1 bison-cattle hybrid fetus by trio binning. Simmental cattle, also known as Fleckvieh due to their red and white spots, originated in central Europe in the 1830s as a triple-purpose breed selected for draught, meat, and dairy production. There are over 50 million Simmental cattle in the world, known today for their fast growth and beef yields. This assembly (ARS_Simm1.0) is similar in length to the other bovine assemblies at 2.86 Gb, with a scaffold N50 of 102 Mb (max scaffold 156.8 Mb) and meets or exceeds the continuity of the best Bos taurus reference assemblies to date.
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http://dx.doi.org/10.1093/jhered/esab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006815PMC
March 2021

Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations.

PLoS One 2021 7;16(1):e0244743. Epub 2021 Jan 7.

Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Background & Aims: Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease.

Methods: We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages.

Results: We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver.

Conclusions: We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244743PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790256PMC
May 2021

Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility.

Science 2020 12;370(6523)

Department of Biology, University of Bari 'Aldo Moro', 70125 Bari, Italy.

The rhesus macaque () is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discovered new lineage-specific genes and expanded gene families that are potentially informative in studies of evolution and disease susceptibility. Whole-genome sequencing (WGS) data from 853 rhesus macaques identified 85.7 million single-nucleotide variants (SNVs) and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay, providing a framework for developing noninvasive NHP models of human disease.
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http://dx.doi.org/10.1126/science.abc6617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818670PMC
December 2020

Hydrobiogeochemistry of Two Catchments in Brazil Under Forest Recovery in an Environmental Services Payment Program.

Environ Monit Assess 2020 Dec 9;193(1). Epub 2020 Dec 9.

USP, Centro de Energia Nuclear na Agricultura, Piracicaba, SP, Brazil.

We investigated the fluvial geochemistry of two catchments at different stages in the forest recovery process which have been a focus of an Environmental Services Payment (ESP) program in Brazil. The Posses (PS) and Salto de Cima (SC) catchments (1200 ha and 1500 ha, respectively) are situated in the municipality of Extrema, Minas Gerais state. Their streams flow into the Jaguari River that supplies part of the water demand of the São Paulo metropolitan area. Samples were collected for chemical analysis and physical-chemical field measures every 2 weeks from January to December 2017. An important pollution point source was discovered in the PS stream related to bovine urine and feces, as well another unidentified source that can be related to a small food processing industry and/or a small fish farm. At the SC stream, on the other hand, there was clear evidence of domestic sewage input. This preliminary study confirmed a limited improvement of the stream water quality in response to recovery of the forest vegetation. Therefore, we recommend that in addition to enhanced monitoring to help distinguish biogeochemical sources and the benefits of land conservation practices, the ESP program should consider controlling point source pollution to accomplish its purpose.
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http://dx.doi.org/10.1007/s10661-020-08773-6DOI Listing
December 2020

Donor-derived renal allograft mucormycosis in a combined liver and kidney transplantation: Case report and review of the literature.

Transpl Infect Dis 2021 Jun 14;23(3):e13534. Epub 2020 Dec 14.

Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Mucormycosis infrequently may present with isolated renal involvement. Among solid organ transplant recipients, renal allograft mucormycosis has been most often associated with medical tourism or transplantation outside of the western world. We report a case of an HIV/HCV co-infected woman who underwent simultaneous liver and kidney transplantation with a Public Health Service increased risk donor organ. 16 days after transplant, she developed massive hematuria and was found to have renal allograft Rhizopus spp. involvement, we surmise to have been from donor-derived infection. Therapy included nephrectomy, debridement, liposomal amphotericin B, and posaconazole with survival. We reviewed PubMed indexed, English-language cases of isolated renal mucormycosis in general, in HIV/AIDS, and from donor-derived renal allograft infections.
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http://dx.doi.org/10.1111/tid.13534DOI Listing
June 2021

Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition.

J Lipid Res 2020 12 2;61(12):1629-1644. Epub 2020 Oct 2.

Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.

NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the "acidic/alternative" pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.
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http://dx.doi.org/10.1194/jlr.RA120000924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707165PMC
December 2020
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