Winter is coming-Temperature affects immune defenses and susceptibility to Batrachochytrium salamandrivorans

PLoS pathogens

2021 Feb 01

Carter, ED;Bletz, MC;Le Sage, M;LaBumbard, B;Rollins-Smith, LA;Woodhams, DC;Miller, DL;Gray, MJ;
PMID: 33600433 | DOI: 10.1371/journal.ppat.1009234

Environmental temperature is a key factor driving various biological processes, including immune defenses and host-pathogen interactions. Here, we evaluated the effects of environmental temperature on the pathogenicity of the emerging fungal pathogen, Batrachochytrium salamandrivorans (Bsal), using controlled laboratory experiments, and measured components of host immune defense to identify regulating mechanisms. We found that adult and juvenile Notophthalmus viridescens died faster due to Bsal chytridiomycosis at 14°C than at 6 and 22°C. Pathogen replication rates, total available proteins on the skin, and microbiome composition likely drove these relationships. Temperature-dependent skin microbiome composition in our laboratory experiments matched seasonal trends in wild N. viridescens, adding validity to these results. We also found that hydrophobic peptide production after two months post-exposure to Bsal was reduced in infected animals compared to controls, perhaps due to peptide release earlier in infection or impaired granular gland function in diseased animals. Using our temperature-dependent susceptibility results, we performed a geographic analysis that revealed N. viridescens populations in the northeastern United States and southeastern Canada are at greatest risk for Bsal invasion, which shifted risk north compared to previous assessments. Our results indicate that environmental temperature will play a key role in the epidemiology of Bsal and provide evidence that temperature manipulations may be a viable disease management strategy.

EMC3 Is Essential for Retinal Organization and Neurogenesis During Mouse Retinal Development

Investigative ophthalmology & visual science

2021 Feb 01

Cao, X;An, J;Cao, Y;Lv, J;Wang, J;Ding, Y;Lin, X;Zhou, X;
PMID: 33605987 | DOI: 10.1167/iovs.62.2.31

We used a mouse model to explore the role of the endoplasmic reticulum membrane protein complex subunit 3 (EMC3) in mammalian retinal development. The transcription pattern of Emc3 in C57BL/6 mice was analyzed by in situ hybridization. To explore the effects of EMC3 absence on retinal development, the Cre-loxP system was used to generate retina-specific Emc3 in knockout mice (Emc3flox/flox, Six3-cre+; CKO). Morphological changes in the retina of E13.5, E17.5, P0.5, and P7 mice were observed via hematoxylin and eosin staining. Immunofluorescence staining was used to assess protein distribution and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining to assess apoptosis changes. Proteins were identified and quantified by Western blotting and proteomic analysis. Electroretinogram (ERG), fundus color photography, and optical coherence tomography were performed on 5-week-old mice to evaluate retinal function and structure. The Emc3 mRNA was widely distributed in the whole retina during development. Loss of retinal EMC3 led to retinal rosette degeneration with mislocalization of cell junction molecules (β-catenin, N-cadherin, and zonula occludens-1) and polarity molecules (Par3 and PKCζ). Endoplasmic reticulum stress and TUNEL apoptosis signals were present in retinal rosette-forming cells. Although the absence of EMC3 promoted the production of photoreceptor cells, 5-week-old mice lost all visual function and had severe retinal morphological degeneration. EMC3 regulates retinal structure by maintaining the polarity of retinal progenitor cells and regulating retinal cell apoptosis.

Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection

Viruses

2021 Jan 15

Everett, HE;Lean, FZX;Byrne, AMP;van Diemen, PM;Rhodes, S;James, J;Mollett, B;Coward, VJ;Skinner, P;Warren, CJ;Bewley, KR;Watson, S;Hurley, S;Ryan, KA;Hall, Y;Simmons, H;Núñez, A;Carroll, MW;Brown, IH;Brookes, SM;
PMID: 33467732 | DOI: 10.3390/v13010113

Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.

G Protein-Biased Mu Opioid Receptor Agonist SR-17018 Has Low In Vivo Efficacy In Non-Human Primates

The Journal of Pain

2023 Apr 01

Ko, M;Ding, H;Kiguchi, N;Zhang, D;Zhang, Y;
| DOI: 10.1016/j.jpain.2023.02.116

SR-17018 was identified as a highly G protein-biased mu opioid peptide (MOP) receptor agonist and lacked MOP agonist-associated adverse effects in mice. The aim of this study was to determine the functional profile of spinal and systemic administration of SR-17018 in non-human primates. In vivo effects of SR-17018 were compared with those of MOP agonists in different intrinsic efficacies, DAMGO, morphine, heroin, and buprenorphine, in behavioral assays established in rhesus monkeys (Macaca mutatta). Nociceptive, itch-scratching, and operant behaviors were measured by experimenters blinded to the dosing conditions. Following intrathecal delivery, SR-17018 (30-300 ug), buprenorphine (3-10 ug), morphine (10-30 ug), and DAMGO (1-3 ug), dose-dependently attenuated capsaicin-induced thermal allodynia (p < 0.05). However, unlike DAMGO and morphine eliciting robust scratching activities, intrathecal SR-17018 and buprenorphine only elicited mild scratching responses, indicating that SR-17018 has low efficacy for activating spinal MOP receptors. In the intravenous drug self-administration assay, heroin (0.3-10 ug/kg/infusion) produced a higher reinforcing strength (abuse liability) as compared to lower reinforcing strengths by SR-17018 (3-30 ug/kg/infusion) and buprenorphine (1-10 ug/kg/infusion) in primates under the progressive-ratio schedule of reinforcement (p < 0.05). The intrathecal opioid-induced itch and intravenous drug self-administration have been documented to distinguish MOP receptor agonists with different intrinsic efficacies. Our findings reveal that in vivo apparent low efficacy of SR-17018 is similar to that of a MOP partial agonist buprenorphine measured by the primate assays with translation relevance. Such a low intrinsic efficacy explains its improved side-effect profile of a highly G protein-biased MOP agonist, S

Neuron-Keratinocyte Communication in the Epidermis in Painful Diabetic Neuropathy

The Journal of Pain

2022 May 01

George, D;Jayaraj, N;Belmadani, A;Ren, D;Miller, R;Menichella, D;
| DOI: 10.1016/j.jpain.2022.03.142

Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes. PDN is characterized by small-fiber degeneration, which can progress to complete loss of cutaneous innervation and is accompanied by neuropathic pain. Uncovering the mechanisms underlying axonal degeneration in PDN remains a major challenge to finding effective and disease-modifying therapies. Sensory nerve afferents normally extend into the epidermis in close juxtaposition to keratinocytes but degenerate in diabetic skin. Our aim is to identify the changes in gene expression profiles and the interactions between dorsal root ganglion (DRG) neurons and keratinocytes to explore the mechanisms by which keratinocytes communicate with cutaneous afferents and how this communication impacts axonal degeneration underlying neuropathic pain in PDN. We used a mouse model of PDN where mice were fed a regular diet (RD, 11% fat) or a high-fat diet (HFD, 42% fat) for 10 weeks during which these mice develop glucose intolerance, mechanical allodynia, small fiber neuropathy. Using a single-cell RNA (scRNA-seq) sequencing approach we captured DRG and keratinocytes gene expression profiles and generated interactome maps. scRNA-seq identified both neuronal and non-neuronal clusters and several differentially expressed genes between RD and HFD from the DRG. We were able to identify several clusters of immune cells and keratinocytes at different stages of differentiation. scRNA-seq results were validated using RNAscope on DRG and skin frozen sections. Moreover, we generated interactome maps between DRG neurons and the peripheral cells to highlight ligand-receptor interactions and we looked to identify genes that were differentially expressed in these interactions. Taken together our data highlights the importance of studying neurons in conjunction with the cells in the tissues with which they interact to identify ligand-receptor interactions that may lead to the identification of neuron signaling in a chronic pain state such as PDN. Grant support from 1R01AR77691-01.

C5aR1 Mediates the Progression of Inflammatory Responses in the Brain of Rats in the Early Stage after Ischemia and Reperfusion

ACS chemical neuroscience

2021 Nov 03

Shi, Y;Jin, Y;Li, X;Chen, C;Zhang, Z;Liu, X;Deng, Y;Fan, X;Wang, C;
PMID: 34637270 | DOI: 10.1021/acschemneuro.1c00244

C5a receptor 1 (C5aR1) can induce a strong inflammatory response to an injury. Targeting C5aR1 has emerged as a novel anti-inflammatory therapeutic method. However, the role of C5aR1 in cerebral ischemia and reperfusion (I/R) injury and the definitive mechanism have not been elucidated clearly. Here, we determined whether C5aR1 signaling was essential to the post-ischemic inflammation and brain injury and whether it is a valid target for therapeutic blockade by using soluble receptor antagonist PMX53 in the early stage after I/R injury. In an in vitro model (oxygen and glucose deprivation and reperfusion, OGD/R) and in vivo model (middle cerebral artery occlusion and reperfusion, MCAO/R) of I/R, the neuronal cells of rats showed significantly up-regulated gene expression of C5aR1, and a notable inflammatory response was demonstrated with elevated tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6. Inhibition of C5aR1 by PMX53 treatment significantly reduced cell injury and inflammation and promoted brain function recovery. Further mechanism studies showed that inhibiting C5aR1 by PMX53 protected the rats from MCAO/R injury, decreased cell inflammation, and apoptosis via inhibiting the TLR4 and NF-κB signaling pathway and reducing the production of TNF-α, IL-1β, and IL-6 in MCAO/R rats. In addition, manipulation of the C5aR1 gene expression in vitro displayed that the inflammatory cascade signals including TLR4, TNF-α, IL-1β, and IL-6 were coincidently regulated with the regulation of C5aR1 expression levels. Thus, our results demonstrated a pathogenic role for C5aR1 in the progression of brain injury and inflammation response following I/R injury. Our study clearly demonstrated that C5aR1 inhibition might be an effective treatment strategy for ischemic stroke.

Muscarinic M4 and M5 receptor subtypes in the ventral subiculum differentially modulate alcohol seeking vs consumption in male alcohol preferring rats

British journal of pharmacology

2021 May 03

Walker, LC;Huckstep, KL;Chen, NA;Hand, LJ;Lindsley, CW;Langmead, CJ;Lawrence, AJ;
PMID: 33942300 | DOI: 10.1111/bph.15513

Muscarinic acetylcholine receptors (mAChRs) mediate alcohol consumption and seeking in rats, and while M4 and M5 mAChRs have recently been implicated to mediate these behaviours in the striatum, their role in other regions remain unknown. The ventral tegmental area (VTA) and ventral subiculum (vSub) both densely express M4 and M5 mAChRs and modulate alcohol seeking via their projections to the nucleus accumbens shell (AcbSh). In Indiana alcohol preferring (iP) male rats we examined Chrm4 (M4 ) and Chrm5 (M5 ) expression in the VTA and vSub following long-term alcohol consumption and abstinence using RT-qPCR. Next, using a combination of retrograde tracing and RNAscope, we examined the localisation of Chrm4 and Chrm5 on vSub cells that project to the AcbSh. Using selective allosteric modulators, we examined the functional role of M4 and M5 mAChRs within the vSub in alcohol consumption, context-induced alcohol seeking, locomotor activity and food/water consumption. Long-term alcohol and abstinence dysregulated mAChR gene expression in the vSub, not VTA. Chrm4 was downregulated following long-term alcohol and abstinence, while Chrm5 was upregulated following long-term alcohol consumption. In line with these data, intra-vSub M4 positive allosteric modulator (VU0467154) reduced context-induced alcohol seeking, but not motivation for alcohol self-administration, while M5 negative allosteric modulator (ML375) reduced initial motivation for alcohol self-administration, but not context-induced alcohol seeking. Collectively our data highlight alcohol-induced cholinergic dysregulation in the vSub and distinct roles for M4 and M5 mAChR allosteric modulators to reduce alcohol consumption or seeking. This article is protected by

Comparative pathology of VIC01 isolate and Omicron variant of SARS-CoV-2 infection, including a rechallenge model, in the Golden Syrian hamster

Journal of Comparative Pathology

2023 May 01

Rayner, E;Ryan, K;Hall, Y;Hunter, L;Kennard, C;Hughes, J;Bodes, J;
| DOI: 10.1016/j.jcpa.2023.03.024

Introduction: The emergence of variants such as Omicron has raised questions regarding their comparative pathogenicity, infectivity and ability to circumvent naturally acquired and vaccine-induced immunity. The Golden Syrian hamster (Mesocricetus auratus) has become the established model for studying SARS-CoV-2 infection, with endpoints providing discriminatory power for countermeasure efficacy. The Omicron variant was compared with ancestral SARS-CoV-2 (VIC01) to evaluate comparative disease severity and to investigate protection against rechallenge. Materials and methods: Four groups of six hamsters were challenged/re-challenged intranasally with SARS-CoV-2(5E+04 PFU). Hamsters were euthanized at 7 days post challenge (dpc) or re-challenged. Lung and nasal cavity samples were fixed in 10% neutral-buffered formalin and processed to slides. In-situ hybridization (RNAscope) was used to detect viral RNA in tissues. Subjective and quantitative methods were employed to assess type and severity of microscopic changes. Results: Severity of pathological lesions and quantity of viral RNA was significantly reduced in both lungs and nasal cavity of animals infected with Omicron, as compared with VIC01, at 7 dpc. In the animals re-challenged with either Omicron or VIC01, minimal to mild lesions in the lungs, mostly pneumocyte type II proliferation, was observed, and viral RNA was not detected in the lungs or nasal cavity from any of these groups. Conclusions: Infection with Omicron in naïve Golden Syrian hamsters resulted in less severe disease than a comparable dose of VIC01. Furthermore, convalescent immunity against prototypical SARS-CoV-2 appears cross-protective against Omicron in this animal model.

Ethanol-induced suppression of GIRK-dependent signaling in the basal amygdala

Biological psychiatry

2023 Apr 15

Fernandez de Velasco, EM;Tipps, ME;Haider, B;Souders, A;Aguado, C;Rose, TR;Vo, BN;DeBaker, MC;Luján, R;Wickman, K;
PMID: 37068702 | DOI: 10.1016/j.biopsych.2023.04.006

The basolateral amygdala (BLA) regulates mood and associative learning and has been linked to the development and persistence of alcohol use disorder (AUD). The GABAB receptor (GABABR) is a promising therapeutic target for AUD, and previous work suggests that exposure to ethanol and other drugs can alter neuronal GABABR-dependent signaling. The effect of ethanol on GABABR-dependent signaling in the BLA is unknown.GABABR-dependent signaling in the mouse BLA was examined using slice electrophysiology following repeated ethanol exposure. Neuron-specific viral genetic manipulations were then used to understand the relevance of ethanol-induced neuroadaptations in the BA to mood-related behavior.The somatodendritic inhibitory effect of GABABR activation on principal neurons in the basal (BA) but not lateral (LA) sub-region of the BLA was diminished following ethanol exposure. This adaptation was attributable to the suppression of G protein-gated inwardly rectifying K+ (GIRK) channel activity and was mirrored by a re-distribution of GABABR and GIRK channels from the surface membrane to internal sites. While GIRK1 and GIRK2 subunits are critical for GIRK channel formation in BA principal neurons, GIRK3 is necessary for the ethanol-induced neuroadaptation. Viral suppression of GIRK channel activity in BA principal neurons from ethanol-naïve mice recapitulated some mood-related behaviors observed in C57BL/6J mice during ethanol withdrawal.The ethanol-induced suppression of GIRK-dependent signaling in BA principal neurons contributes to some of the mood-related behaviors associated with ethanol withdrawal in mice. Approaches designed to prevent this neuroadaptation and/or strengthen GIRK-dependent signaling may prove useful for treatment of AUD.

Lipid metabolism in dopaminergic neurons influences light entrainment

Journal of neurochemistry

2023 Feb 23

Fernandez, RF;Wilson, ES;Diaz, V;Martínez-Gardeazabal, J;Foguth, R;Cannon, JR;Jackson, SN;Hermann, BP;Eells, JB;Ellis, JM;
PMID: 36815399 | DOI: 10.1111/jnc.15793

Dietary lipids, particularly omega-3 polyunsaturated fatty acids, are speculated to impact behaviors linked to the dopaminergic system, such as movement and control of circadian rhythms. However, the ability to draw a direct link between dopaminergic omega-3 fatty acid metabolism and behavioral outcomes has been limited to the use of diet-based approaches, which are confounded by systemic effects. Here, neuronal lipid metabolism was targeted in a diet-independent manner by manipulation of long-chain acyl-CoA synthetase 6 (ACSL6) expression. ACSL6 performs the initial reaction for cellular fatty acid metabolism and prefers the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). The loss of Acsl6 in mice (Acsl6-/- ) depletes neuronal membranes of DHA content and results in phenotypes linked to dopaminergic control, such as hyperlocomotion, impaired short-term spatial memory, and imbalances in dopamine neurochemistry. To investigate the role of dopaminergic ACSL6 on these outcomes, a dopaminergic neuron-specific ACSL6 knockout mouse was generated (Acsl6DA-/- ). Acsl6DA-/- mice demonstrated hyperlocomotion and imbalances in striatal dopamine neurochemistry. Circadian rhythms of both the Acsl6-/- and the Acsl6DA-/- mice were similar to control mice under basal conditions. However, upon light entrainment, a mimetic of jet lag, both the complete knockout of ACSL6 and the dopaminergic-neuron-specific loss of ACSL6 resulted in a longer recovery to entrainment compared to control mice. In conclusion, these data demonstrate that ACSL6 in dopaminergic neurons alters dopamine metabolism and regulation of light entrainment suggesting that DHA metabolism mediated by ACSL6 plays a role in dopamine neuron biology.

Epigenetic priming of immune/inflammatory pathways activation and abnormal activity of cell cycle pathway in a perinatal model of white matter injury

Cell death & disease

2022 Dec 13

Schang, AL;Van Steenwinckel, J;Ioannidou, ZS;Lipecki, J;Rich-Griffin, C;Woolley-Allen, K;Dyer, N;Le Charpentier, T;Schäfer, P;Fleiss, B;Ott, S;Sabéran-Djoneidi, D;Mezger, V;Gressens, P;
PMID: 36513635 | DOI: 10.1038/s41419-022-05483-4

Prenatal inflammatory insults accompany prematurity and provoke diffuse white matter injury (DWMI), which is associated with increased risk of neurodevelopmental pathologies, including autism spectrum disorders. DWMI results from maturation arrest of oligodendrocyte precursor cells (OPCs), a process that is poorly understood. Here, by using a validated mouse model of OPC maturation blockade, we provide the genome-wide ID card of the effects of neuroinflammation on OPCs that reveals the architecture of global cell fate issues underlining their maturation blockade. First, we find that, in OPCs, neuroinflammation takes advantage of a primed epigenomic landscape and induces abnormal overexpression of genes of the immune/inflammatory pathways: these genes strikingly exhibit accessible chromatin conformation in uninflamed OPCs, which correlates with their developmental, stage-dependent expression, along their normal maturation trajectory, as well as their abnormal upregulation upon neuroinflammation. Consistently, we observe the positioning on DNA of key transcription factors of the immune/inflammatory pathways (IRFs, NFkB), in both unstressed and inflamed OPCs. Second, we show that, in addition to the general perturbation of the myelination program, neuroinflammation counteracts the physiological downregulation of the cell cycle pathway in maturing OPCs. Neuroinflammation therefore perturbs cell identity in maturing OPCs, in a global manner. Moreover, based on our unraveling of the activity of genes of the immune/inflammatory pathways in prenatal uninflamed OPCs, the mere suppression of these proinflammatory mediators, as currently proposed in the field, may not be considered as a valid neurotherapeutic strategy.

Peripheral sensory neuron CB2 cannabinoid receptors are necessary for both CB2-mediated antinociceptive efficacy and sparing of morphine tolerance in a mouse model of anti-retroviral toxic neuropathy

Pharmacological research

2022 Nov 20

Carey, LM;Xu, Z;Rajic, G;Makriyannis, A;Romero, J;Hillard, C;Mackie, K;Hohmann, AG;
PMID: 36417942 | DOI: 10.1016/j.phrs.2022.106560

Painful peripheral neuropathy is a common neurological complication associated with human immunodeficiency virus (HIV) infection and anti-retroviral therapy. We characterized the impact of two CB2 cannabinoid agonists (AM1710 and LY2828360 - ligands differing in signaling bias and CNS penetration) on neuropathic nociception induced by the antiretroviral agent Zalcitabine (2',3'-dideoxycytidine; ddC). We also used a conditional knockout approach to identify cell types mediating CB2 agonist-induced antinociceptive efficacy and sparing of morphine tolerance. AM1710 and LY2828360 alleviated ddC-induced neuropathic nociception in mice of both sexes. These benefits were absent in global CB2 knockout mice, which exhibited robust morphine antinociception. Like morphine, AM1710 blunted ddC-induced increases in proinflammatory cytokine (IL-1β, TNF-α) and chemokine (CCL2) mRNA expression levels. We generated advillinCre/+;CB2f/f conditional knockout mice to ascertain the role of CB2 localized to primary sensory neurons in CB2-mediated therapeutic effects. Antinociceptive efficacy of both AM1710 and LY2828360, but not reference analgesics, were absent in advillinCre/+;CB2f/f mice, which exhibited robust ddC-induced neuropathy. In ddC-treated CB2f/f mice, LY2828360 suppressed development of morphine tolerance and reversed established morphine tolerance, albeit with greater efficacy in male compared to female mice. LY2828360 failed to block or reverse morphine tolerance in advillinCre/+;CB2f/f mice. The present studies indicate that CB2 activation may alleviate HIV-associated antiretroviral neuropathy and identify a previously unreported mechanism through which CB2 activation produces antinociceptive efficacy. Our results also provide the first evidence that a CB2 agonist can reverse established morphine tolerance and demonstrate that CB2 localized to peripheral sensory neurons mediates the opioid tolerance sparing efficacy of CB2 agonists.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
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tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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