Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice

Frontiers in pharmacology

2023 Jun 14

Berezin, CT;Bergum, N;Torres Lopez, GM;Vigh, J;
PMID: 37388441 | DOI: 10.3389/fphar.2023.1206104

Opioids are effective analgesics for treating moderate to severe pain, however, their use must be weighed against their dangerous side effects. Investigations into opioid pharmacokinetics provide crucial information regarding both on- and off-target drug effects. Our recent work showed that morphine deposits and accumulates in the mouse retina at higher concentrations than in the brain upon chronic systemic exposure. We also found reduced retinal expression of P-glycoprotein (P-gp), a major opioid extruder at the blood-brain barrier (BBB). Here, we systematically interrogated the expression of three putative opioid transporters at the blood-retina barrier (BRB): P-gp, breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2). Using immunohistochemistry, we found robust expression of P-gp and Bcrp, but not Mrp2, at the inner BRB of the mouse retina. Previous studies have suggested that P-gp expression may be regulated by sex hormones. However, upon acute morphine treatment we found no sex differences in morphine deposition levels in the retina or brain, nor on transporter expression in the retinas of males and females with a high or low estrogen:progesterone ratio. Importantly, we found that P-gp, but not Bcrp, expression significantly correlated with morphine concentration in the retina, suggesting P-gp is the predominant opioid transporter at the BRB. In addition, fluorescence extravasation studies revealed that chronic morphine treatment did not alter the permeability of either the BBB or BRB. Together, these data suggest that reduced P-gp expression mediates retinal morphine accumulation upon systemic delivery, and in turn, potential effects on circadian photoentrainment.

Optimizing Precision Medicine for Breast Cancer Brain Metastases with Functional Drug Response Assessment

Cancer research communications

2023 Jun 01

Morikawa, A;Li, J;Ulintz, P;Cheng, X;Apfel, A;Robinson, D;Hopkins, A;Kumar-Sinha, C;Wu, YM;Serhan, H;Verbal, K;Thomas, D;Hayes, DF;Chinnaiyan, AM;Baladandayuthapani, V;Heth, J;Soellner, MB;Merajver, SD;Merrill, N;
PMID: 37377606 | DOI: 10.1158/2767-9764.CRC-22-0492

The development of novel therapies for brain metastases is an unmet need. Brain metastases may have unique molecular features that could be explored as therapeutic targets. A better understanding of the drug sensitivity of live cells coupled to molecular analyses will lead to a rational prioritization of therapeutic candidates. We evaluated the molecular profiles of 12 breast cancer brain metastases (BCBM) and matched primary breast tumors to identify potential therapeutic targets. We established six novel patient-derived xenograft (PDX) from BCBM from patients undergoing clinically indicated surgical resection of BCBM and used the PDXs as a drug screening platform to interrogate potential molecular targets. Many of the alterations were conserved in brain metastases compared with the matched primary. We observed differential expressions in the immune-related and metabolism pathways. The PDXs from BCBM captured the potentially targetable molecular alterations in the source brain metastases tumor. The alterations in the PI3K pathway were the most predictive for drug efficacy in the PDXs. The PDXs were also treated with a panel of over 350 drugs and demonstrated high sensitivity to histone deacetylase and proteasome inhibitors. Our study revealed significant differences between the paired BCBM and primary breast tumors with the pathways involved in metabolisms and immune functions. While molecular targeted drug therapy based on genomic profiling of tumors is currently evaluated in clinical trials for patients with brain metastases, a functional precision medicine strategy may complement such an approach by expanding potential therapeutic options, even for BCBM without known targetable molecular alterations.Examining genomic alterations and differentially expressed pathways in brain metastases may inform future therapeutic strategies. This study supports genomically-guided therapy for BCBM and further investigation into incorporating real-time functional evaluation will increase confidence in efficacy estimations during drug development and predictive biomarker assessment for BCBM.

The Midbody and Midbody Remnant are Assembly Sites for RNA and Localized Translation

Available at SSRN

2023 Jan 30

Park, S;Dahn, R;Kurt, E;Presle, A;VandenHeuvel, K;Moravec, C;Jambhekar, A;Olukoga, O;Shepherd, J;Echard, A;Blower, M;Skop, A;
| DOI: 10.2139/ssrn.4318824

The midbody (MB) is a transient structure at the spindle midzone that is required for cytokinesis, the terminal stage of cell division. Long ignored as a vestigial remnant of cytokinesis, we now know MBs are released post-abscission as extracellular vesicles called MB remnants (MBRs) and can modulate cell proliferation, fate decisions, tissue polarity, neuronal architecture, and tumorigenic behavior. Here, we demonstrate that the MB matrix—the structurally amorphous MB core of unknown composition—is the site of ribonucleoprotein assembly and is enriched in mRNAs that encode proteins involved in cell fate, oncogenesis, and pluripotency, that we are calling the MB granule. Using a quantitative transcriptomic approach, we identified a population of mRNAs enriched in mitotic MBs and confirmed their presence in signaling MBR vesicles released by abscission. The MB granule is unique in that it is translationally active, contains both small and large ribosomal subunits, and has both membrane-less and membranebound states. Both MBs and post-abscission MBRs are sites of spatiotemporally regulated translation, which is initiated when nascent daughter cells re-enter G1 and continues after extracellular release. We demonstrate that the MB is the assembly site of an RNP granule. MKLP1 and ARC are necessary for the localization and translation of RNA in the MB dark zone, whereas ESCRT-III was necessary to maintain translation levels in the MB. Our data suggest a model in which the MB functions as a novel RNA-based organelle with a uniquely complex life cycle. We present a model in which the assembly and transfer of RNP complexes are central to post-mitotic MBR function and suggest the MBR serves as a novel mode of RNA-based intercellular communication with a defined biogenesis that is coupled to abscission, and inherently links cell division status with signaling capacity. To our knowledge, this is the first example of an autonomous extracellular vesicle with active translation activity.

Sourcing high tissue quality brains from deceased wild primates with known socio-ecology

Methods in Ecology and Evolution

2022 May 17

Graßle, T;Crockford, C;Eichner, C;
| DOI: 10.1111/2041-210x.14039/v1/review3

The selection pressures that drove dramatic encephalisation processes through the mammal lineage remain elusive, as does knowledge of brain structure reorganisation through this process. In particular, considerable structural brain changes are present across the primate lineage, culminating in the complex human brain that allows for unique behaviours such as language and sophisticated tool use. To understand this evolution, a diverse sample set of humans' closest relatives with varying socio-ecologies is needed. However, current brain banks predominantly curate brains from primates that died in zoological gardens. We try to address this gap by establishing a field pipeline mitigating the challenges associated with brain extractions of wild primates in their natural habitat.The success of our approach is demonstrated by our ability to acquire a novel brain sample of deceased primates with highly variable socio-ecological exposure and a particular focus on wild chimpanzees. Methods in acquiring brain tissue from wild settings are comprehensively explained, highlighting the feasibility of conducting brain extraction procedures under strict biosafety measures by trained veterinarians in field sites.Brains are assessed at a fine-structural level via high-resolution MRI and state-of-the-art histology. Analyses confirm that excellent tissue quality of primate brains sourced in the field can be achieved with a comparable tissue quality of brains acquired from zoo-living primates.Our field methods are noninvasive, here defined as not harming living animals, and may be applied to other mammal systems than primates. In sum, the field protocol and methodological pipeline validated here pose a major advance for assessing the influence of socio-ecology on medium to large mammal brains, at both macro- and microstructural levels as well as aiding with the functional annotation of brain regions and neuronal pathways via specific behaviour assessments

PhP.B Enhanced Adeno-Associated Virus Mediated-Expression Following Systemic Delivery or Direct Brain Administration

Frontiers in bioengineering and biotechnology

2021 Aug 03

Pietersz, KL;Plessis, FD;Pouw, SM;Liefhebber, JM;van Deventer, SJ;Martens, GJM;Konstantinova, PS;Blits, B;
PMID: 34414171 | DOI: 10.3389/fbioe.2021.679483

Of the adeno-associated viruses (AAVs), AAV9 is known for its capability to cross the blood-brain barrier (BBB) and can, therefore, be used as a noninvasive method to target the central nervous system. Furthermore, the addition of the peptide PhP.B to AAV9 increases its transduction across the BBB by 40-fold. Another neurotropic serotype, AAV5, has been shown as a gene therapeutic delivery vehicle to ameliorate several neurodegenerative diseases in preclinical models, but its administration requires invasive surgery. In this study, AAV9-PhP.B and AAV5-PhP.B were designed and produced in an insect cell-based system. To AAV9, the PhP.B peptide TLAVPFK was added, whereas in AAV5-PhP.B (AQTLAVPFKAQAQ), with AQ-AQAQ sequences used to swap with the corresponding sequence of AAV5. The addition of PhP.B to AAV5 did not affect its capacity to cross the mouse BBB, while increased transduction of liver tissue was observed. Then, intravenous (IV) and intrastriatal (IStr) delivery of AAV9-PhP.B and AAV5 were compared. For AAV9-PhP.B, similar transduction and expression levels were achieved in the striatum and cortex, irrespective of the delivery method used. IStr administration of AAV5 resulted in significantly higher amounts of vector DNA and therapeutic miRNA in the target regions such as striatum and cortex when compared with an IV administration of AAV9-PhP.B. These results illustrate the challenge in developing a vector that can be delivered noninvasively while achieving a transduction level similar to that of direct administration of AAV5. Thus, for therapeutic miRNA delivery with high local expression requirements, intraparenchymal delivery of AAV5 is preferred, whereas a humanized AAV9-PhP.B may be useful when widespread brain (and peripheral) transduction is needed.

Multiscale characterization of four Tropomyosin-1 variants of unknown significance

Biophysical Journal

2022 Feb 01

Rynkiewicz, M;Creso, J;Li, X;Sewanan, L;Liu, D;Barry, M;Moore, J;Lehman, W;Campbell, S;
| DOI: 10.1016/j.bpj.2021.11.1470

Mutations in proteins forming the contractile apparatus of cardiac muscle can alter muscle function, leading to a hypercontractile or a hypocontractile state of the heart. These mutational insults can also lead to secondary cardiac remodeling and disease states over time, resulting in either hypertrophic cardiomyopathy (HCM), affecting about 1 in 500 individuals, or dilated cardiomyopathy (DCM), affecting about 1 in 250 individuals. We are applying a broad range of techniques to follow the initial atomic-level insults to tissue-level remodeling and function in an effort to better understand mechanisms of disease. Here, we characterize four variants of unknown significance in tropomyosin-1 (Tpm1.1), a key regulatory protein on muscle thin filaments, using a combination of molecular modeling techniques, in vitro motility assays, and analysis in whole tissue derived from engineered induced-pluripotent stem cells. First, a list of about 20 variants of unknown significance were analyzed computationally using molecular dynamics and energy minimization calculations to predict each mutant’s effects on Tpm1.1 structure and association with thin filament proteins. From this analysis, four mutations (A102D, D258E, K233N, and A239T) were selected for further study. A multiscale model of myofilament activation was then used to synthesize key parameters distilled from atomistic simulations, allowing ab initio predictions of the impact of each variant on myofilament calcium sensitivity and twitch force phenotype. These predictions were then tested for each variant via in vitro motility assays and human engineered heart tissues virally expressing mutant Tpm1.1. A comparison between predicted and actual variant phenotypes reveals robust progress toward our long-term goal of computational prediction of disease risk for novel Tpm1.1 variants while simultaneously highlighting new challenges and opportunities with this method.

Abnormal activation of yap/Taz contributes to the pathogenesis of tuberous sclerosis complex

Human molecular genetics

2022 Jan 06

Terry, BK;Park, R;Cho, SH;Crino, PB;Kim, S;
PMID: 34999833 | DOI: 10.1093/hmg/ddab374

The multi-systemic genetic disorder tuberous sclerosis complex (TSC) impacts multiple neurodevelopmental processes including neuronal morphogenesis, neuronal migration, myelination, and gliogenesis. These alterations contribute to the development of cerebral cortex abnormalities and malformations. Although TSC is caused by mTORC1 hyperactivation, cognitive and behavioral impairments are not improved through mTORC1 targeting, making the study of the downstream effectors of this complex important for understanding the mechanisms underlying TSC. As mTORC1 has been shown to promote the activity of the transcriptional co-activator Yap, we hypothesized that altered Yap/Taz signaling contributes to the pathogenesis of TSC. We first observed that the level of Yap/Taz are increased in a human cortical tuber sample and in embryonic cortices of Tsc2 conditional knockout (cKO) mice. Next, to determine how abnormal upregulation of Yap/Taz impacts the neuropathology of TSC, we deleted Yap/Taz in Tsc2 cKO mice. Importantly, Yap/Taz/Tsc2 tcKO animals show reduced cortical thickness and cortical neuron cell size, despite the persistence of high mTORC1 activity, suggesting that Yap/Taz play a downstream role in cytomegaly. Furthermore, Yap/Taz/Tsc2 tcKO significantly restored cortical and hippocampal lamination defects and reduced hippocampal heterotopia formation. Finally, the loss of Yap/Taz increased the distribution of myelin basic protein in Tsc2 cKO animals, consistent with an improvement in myelination. Overall, our results indicate that targeting Yap/Taz lessens the severity of neuropathology in a TSC animal model. This study is the first to implicate Yap/Taz as contributors to cortical pathogenesis in TSC and therefore as potential novel targets in the treatment of this disorder.

Neonates and COVID-19: state of the art: Neonatal Sepsis series

Pediatric research

2021 Dec 28

Ryan, L;Plötz, FB;van den Hoogen, A;Latour, JM;Degtyareva, M;Keuning, M;Klingenberg, C;Reiss, IKM;Giannoni, E;Roehr, C;Gale, C;Molloy, EJ;
PMID: 34961785 | DOI: 10.1038/s41390-021-01875-y

The SARS-CoV-2 pandemic has had a significant impact worldwide, particularly in middle- and low-income countries. While this impact has been well-recognized in certain age groups, the effects, both direct and indirect, on the neonatal population remain largely unknown. There are placental changes associated, though the contributions to maternal and fetal illness have not been fully determined. The rate of premature delivery has increased and SARS-CoV-2 infection is proportionately higher in premature neonates, which appears to be related to premature delivery for maternal reasons rather than an increase in spontaneous preterm labor. There is much room for expansion, including long-term data on outcomes for affected babies. Though uncommon, there has been evidence of adverse events in neonates, including Multisystem Inflammatory Syndrome in Children, associated with COVID-19 (MIS-C). There are recommendations for reduction of viral transmission to neonates, though more research is required to determine the role of passive immunization of the fetus via maternal vaccination. There is now considerable evidence suggesting that the severe visitation restrictions implemented early in the pandemic have negatively impacted the care of the neonate and the experiences of both parents and healthcare professionals alike. Ongoing collaboration is required to determine the full impact, and guidelines for future management. IMPACT: Comprehensive review of current available evidence related to impact of the COVID-19 pandemic on neonates, effects on their health, impact on their quality of care and indirect influences on their clinical course, including comparisons with other age groups. Reference to current evidence for maternal experience of infection and how it impacts the fetus and then neonate. Outline of the need for ongoing research, including specific areas in which there are significant gaps in knowledge.

High Systemic Type I Interferon Activity is Associated with Active Class III/IV Lupus Nephritis

The Journal of rheumatology

2021 Nov 15

Iwamoto, T;Dorschner, JM;Selvaraj, S;Mezzano, V;Jensen, MA;Vsetecka, D;Amin, S;Makol, A;Osborn, T;Moder, K;Chowdhary, VR;Izmirly, P;Belmont, HM;Clancy, RM;Buyon, JP;Wu, M;Loomis, CA;Niewold, TB;
PMID: 34782453 | DOI: 10.3899/jrheum.210391

Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the impact of IFN in LN.221 systemic lupus erythematosus (SLE) patients were studied. Serum IFN activity was measured by WISH bioassay. mRNA in-situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, interferon-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C or BDCA2). Podocyte cell line gene expression was measured by real-time PCR.Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (OR=5.48, p=4.0x10-7). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely co-localized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules.Systemic high IFN is involved in the pathogenesis of severe LN. We do not find co-localization of pDCs with IFN signature in renal tissue, and instead observe the greatest intensity of IFN signature in glomerular areas, which could suggest a blood source of IFN.

Engineering Cancer Antigen-Specific T Cells to Overcome the Immunosuppressive Effects of TGF-β

Journal of immunology (Baltimore, Md. : 1950)

2022 Jan 01

Silk, JD;Abbott, RJM;Adams, KJ;Bennett, AD;Brett, S;Cornforth, TV;Crossland, KL;Figueroa, DJ;Jing, J;O'Connor, C;Pachnio, A;Patasic, L;Peredo, CE;Quattrini, A;Quinn, LL;Rust, AG;Saini, M;Sanderson, JP;Steiner, D;Tavano, B;Viswanathan, P;Wiedermann, GE;Wong, R;Jakobsen, BK;Britten, CM;Gerry, AB;Brewer, JE;
PMID: 34853077 | DOI: 10.4049/jimmunol.2001357

Adoptive T cell therapy with T cells expressing affinity-enhanced TCRs has shown promising results in phase 1/2 clinical trials for solid and hematological tumors. However, depth and durability of responses to adoptive T cell therapy can suffer from an inhibitory tumor microenvironment. A common immune-suppressive agent is TGF-β, which is secreted by tumor cells and cells recruited to the tumor. We investigated whether human T cells could be engineered to be resistant to inhibition by TGF-β. Truncating the intracellular signaling domain from TGF-β receptor (TGFβR) II produces a dominant-negative receptor (dnTGFβRII) that dimerizes with endogenous TGFβRI to form a receptor that can bind TGF-β but cannot signal. We previously generated specific peptide enhanced affinity receptor TCRs recognizing the HLA-A*02-restricted peptides New York esophageal squamous cell carcinoma 1 (NY-ESO-1)157-165/l-Ag family member-1A (TCR: GSK3377794, formerly NY-ESO-1c259) and melanoma Ag gene A10254-262 (TCR: ADP-A2M10, formerly melanoma Ag gene A10c796). In this article, we show that exogenous TGF-β inhibited in vitro proliferation and effector functions of human T cells expressing these first-generation high-affinity TCRs, whereas inhibition was reduced or abolished in the case of second-generation TCRs coexpressed with dnTGFβRII (e.g., GSK3845097). TGF-β isoforms and a panel of TGF-β-associated genes are overexpressed in a range of cancer indications in which NY-ESO-1 is commonly expressed, particularly in synovial sarcoma. As an example, immunohistochemistry/RNAscope identified TGF-β-positive cells close to T cells in tumor nests and stroma, which had low frequencies of cells expressing IFN-γ in a non-small cell lung cancer setting. Coexpression of dnTGFβRII may therefore improve the efficacy of TCR-transduced T cells.

Yap Promotes Noncanonical Wnt Signals from Cardiomyocytes for Heart Regeneration

Circulation research

2021 Aug 23

Liu, S;Tang, L;Zhao, X;Nguyen, B;Heallen, TR;Li, M;Wang, J;Wang, J;Martin, JF;
PMID: 34424032 | DOI: 10.1161/CIRCRESAHA.121.318966

Rationale: During neonatal heart regeneration, the fibrotic response, which is required to prevent cardiac rupture, resolves via poorly understood mechanisms. Deletion of the Hippo pathway gene Sav in adult CMs increases Yap activity and promotes cardiac regeneration, partly by inducing fibrosis resolution. Deletion of Yap in neonatal cardiomyocytes (CMs) leads to increased fibrosis and loss of neonatal heart regeneration, suggesting that Yap inhibits fibrosis by regulating intercellular signaling from CMs to cardiac fibroblasts (CFs). Objective: We investigated the role of Wntless (Wls), which is a direct target gene of Yap, in communication between CMs and CFs during neonatal heart regeneration. Methods and Results: We generated two mouse models to delete Wls specifically in CMs (Myh6-Cas9 combined with AAV9-Wls-gRNAs, and Myh6cre-ERT2/+; Wlsflox/flox mouse). Reanalysis of single-cell RNA-sequencing data revealed that Wnt ligands are expressed in CMs, whereas Wnt receptors are expressed in CFs, suggesting that Wnt signaling is directional from CMs to CFs during neonatal heart regeneration. Wls deletion in neonatal hearts disrupted Wnt signaling, showing as reduced noncanonical Wnt signaling in non-CMs. Four weeks after neonatal heart infarction, heart function was measured by echocardiography. Wls deletion in neonatal hearts after myocardial infarction impairs neonatal heart regeneration, marked by decreased contractile function and increased fibrosis. Wls mutant hearts display CF activation, characterized by increased extracellular matrix secretion, inflammation, and CF proliferation. Conclusions: These data indicate that during neonatal heart regeneration, intercellular signaling from CMs to CFs occurs via noncanonical Wnt signaling to rebuild cardiac architecture after myocardial infarction.

Integrative Functional Genomic Analysis of Human PTSD Molecular Pathology and Risk

Biological Psychiatry

2021 May 01

Girgenti, M;Skarica, M;Zhang, J;Wang, J;Friedman, M;Zhao, H;Krystal, J;
| DOI: 10.1016/j.biopsych.2021.02.050

Background PTSD is a multigenic and multifactorial disorder occurring in the aftermath of significant trauma exposure. Recent GWAS have identified many high confidence loci as risk factors for PTSD, which have shed some light on impaired mechanisms. However, there are still fundamental gaps in our understanding of how these risk genes and pathways are interrelated in causing PTSD but are likely reflected in cell type-specific transcriptomic and epigenetic changes in the brain. Therefore, it is necessary to uncover the individual cell type contribution to the molecular pathology of PTSD. Methods We isolated nuclei from human postmortem dorsolateral prefrontal cortex (BA 9/46) from n=50 PTSD, MDD, and controls for single nucleus sequencing. We sequenced RNA from 10,000 nuclei per sample and used RNAscope fluorescence in situ hybridization to validate cell type specific gene expression changes. We performed snATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) on 5000 nuclei to generate disease and control open chromatin maps to compare DNA accessibility. Results These results implicate 19 cell types, in particular inhibitory interneurons and microglia as dysregulated in PTSD brain. Open chromatin profiles matched transcript levels and provided new genomic information and possible functional roles for PTSD risk loci identified by GWAS. Conclusions -Omics technologies have been instrumental in our understanding of the connection between the disruption of particular loci and final molecular pathology of neuropsychiatric disorders. Applying functional genomics approaches to characterize findings from multiple layers of single cell-type studies of postmortem brain tissue may therefore help determine which neurotypical processes are most impacted by PTSD.

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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
Retired Nomenclature
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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