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.

Does SARS-CoV-2 infect cardiomyocytes directly? Yes, it does

Medical Research Journal

2021 Sep 07

Ryszewska, A;Niewiadomski, P;
| DOI: 10.5603/mrj.a2021.0038

Introduction: COVID-19 (Coronavirus disease 2019) appeared in Wuhan, China, at the ending of 2019. The SARS-CoV-2 virus which causes the illness has spread all over the world and caused a pandemic. The first target of the virus is the respiratory tract; however, the COVID-19 may present different types of course. It is known that the SARS-CoV-2 affects multiple organs, including the heart. Cardiac manifestations of COVID-19 include myocarditis, myocardial infarction, heart failure, acute coronar... Morey syndrome, arrhythmia. The authors know about the patients who had only cardiovascular complications due to the COVID-19. Several mechanisms of heart injury are considered and so is the direct infection. Aim of the study: The present review aimed to find out if the SARS-CoV-2 may infect the heart directly and in which mechanism. The review is an information collection considering the SARS-CoV-2 impact on the heart. Material and methods: The authors have made research using the PubMed search engine to find studies and case reports considering the cardiovascular implications of COVID-19. The signs and symptoms in patients with cardiac implications were studied. The authors have also checked if studies explaining does the SARS-CoV-2 affects the heart directly were conducted. Results: SARS-CoV-2 brings several cardiovascular signs such as changes in imaging tests and elevation of several laboratory markers. The changes may suggest myocarditis or mimic cardiac infarction. The SARS-CoV-2 may affect cardiomyocytes indirectly by causing hypoxia and cytokine storm. As the heart tissue presents a high level of ACE2 which is the target of the virus, the SARS-CoV may infect cardiomyocytes directly. The hypothesis was confirmed in endomyocardial biopsies, autopsy, and in vitro studies. Conclusions: The SARS-CoV-2 impacts several organs. The heart may be injured indirectly (hypoxia and cytokine storm) and directly (ACE2 present in the heart), which gives consequences in a clinical course. The direct injury was confirmed in a variety of ways. Less

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.

The thrombin receptor modulates astroglia-neuron trophic coupling and neural repair after spinal cord injury

Glia

2021 Apr 22

Kim, HN;Triplet, EM;Radulovic, M;Bouchal, S;Kleppe, LS;Simon, WL;Yoon, H;Scarisbrick, IA;
PMID: 33887067 | DOI: 10.1002/glia.24012

Excessive activation of the thrombin receptor, protease activated receptor 1 (PAR1) is implicated in diverse neuropathologies from neurodegenerative conditions to neurotrauma. PAR1 knockout mice show improved outcomes after experimental spinal cord injury (SCI), however information regarding the underpinning cellular and molecular mechanisms is lacking. Here we demonstrate that genetic blockade of PAR1 in female mice results in improvements in sensorimotor co-ordination after thoracic spinal cord lateral compression injury. We document improved neuron preservation with increases in Synapsin-1 presynaptic proteins and GAP43, a growth cone marker, after a 30 days recovery period. These improvements were coupled to signs of enhanced myelin resiliency and repair, including increases in the number of mature oligodendrocytes, their progenitors and the abundance of myelin basic protein. These significant increases in substrates for neural recovery were accompanied by reduced astrocyte (Serp1) and microglial/monocyte (CD68 and iNOS) pro-inflammatory markers, with coordinate increases in astrocyte (S100A10 and Emp1) and microglial (Arg1) markers reflective of pro-repair activities. Complementary astrocyte-neuron co-culture bioassays suggest astrocytes with PAR1 loss-of-function promote both neuron survival and neurite outgrowth. Additionally, the pro-neurite outgrowth effects of switching off astrocyte PAR1 were blocked by inhibiting TrkB, the high affinity receptor for brain derived neurotrophic factor. Altogether, these studies demonstrate unique modulatory roles for PAR1 in regulating glial-neuron interactions, including the capacity for neurotrophic factor signaling, and underscore its position at neurobiological intersections critical for the response of the CNS to injury and the capacity for regenerative repair and restoration of function.

PKN1 Is a Novel Regulator of Hippocampal GluA1 Levels

Frontiers in synaptic neuroscience

2021 Feb 05

Safari, MS;Obexer, D;Baier-Bitterlich, G;Zur Nedden, S;
PMID: 33613259 | DOI: 10.3389/fnsyn.2021.640495

Alterations in the processes that control α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression, assembly and trafficking are closely linked to psychiatric and neurodegenerative disorders. We have recently shown that the serine/threonine kinase Protein kinase N1 (PKN1) is a developmentally active regulator of cerebellar synaptic maturation by inhibiting AKT and the neurogenic transcription factor neurogenic differentiation factor-2 (NeuroD2). NeuroD2 is involved in glutamatergic synaptic maturation by regulating expression levels of various synaptic proteins. Here we aimed to study the effect of Pkn1 knockout on AKT phosphorylation and NeuroD2 levels in the hippocampus and the subsequent expression levels of the NeuroD2 targets and AMPAR subunits: glutamate receptor 1 (GluA1) and GluA2/3. We show that PKN1 is expressed throughout the hippocampus. Interestingly, not only postnatal but also adult hippocampal phospho-AKT and NeuroD2 levels were significantly elevated upon Pkn1 knockout. Postnatal and adult Pkn1-/- hippocampi showed enhanced expression of the AMPAR subunit GluA1, particularly in area CA1. Surprisingly, GluA2/3 levels were not different between both genotypes. In addition to higher protein levels, we also found an enhanced GluA1 content in the membrane fraction of postnatal and adult Pkn1-/- animals, while GluA2/3 levels remained unchanged. This points toward a very specific regulation of GluA1 expression and/or trafficking by the novel PKN1-AKT-NeuroD2 axis. Considering the important role of GluA1 in hippocampal development as well as the pathophysiology of several disorders, ranging from Alzheimer's, to depression and schizophrenia, our results validate PKN1 for future studies into neurological disorders related to altered AMPAR subunit expression in the hippocampus.

Long noncoding RNA TINCR is a novel regulator of human bronchial epithelial cell differentiation state

Physiological reports

2021 Feb 01

Omote, N;Sakamoto, K;Li, Q;Schupp, JC;Adams, T;Ahangari, F;Chioccioli, M;DeIuliis, G;Hashimoto, N;Hasegawa, Y;Kaminski, N;
PMID: 33527707 | DOI: 10.14814/phy2.14727

Long-noncoding RNAs (lncRNAs) have numerous biological functions controlling cell differentiation and tissue development. The knowledge about the role of lncRNAs in human lungs remains limited. Here we found the regulatory role of the terminal differentiation-induced lncRNA (TINCR) in bronchial cell differentiation. RNA in situ hybridization revealed that TINCR was mainly expressed in bronchial epithelial cells in normal human lung. We performed RNA sequencing analysis of normal human bronchial epithelial cells (NHBECs) with or without TINCR inhibition and found the differential expression of 603 genes, which were enriched for cell adhesion and migration, wound healing, extracellular matrix organization, tissue development and differentiation. To investigate the role of TINCR in the differentiation of NHBECs, we employed air-liquid interface culture and 3D organoid formation assay. TINCR was upregulated during differentiation, loss of TINCR significantly induced an early basal-like cell phenotype (TP63) and a ciliated cell differentiation (FOXJ1) in late phase and TINCR overexpression suppressed basal cell phenotype and the differentiation toward to ciliated cells. Critical regulators of differentiation such as SOX2 and NOTCH genes (NOTCH1, HES1, and JAG1) were significantly upregulated by TINCR inhibition and downregulated by TINCR overexpression. RNA immunoprecipitation assay revealed that TINCR was required for the direct bindings of Staufen1 protein to SOX2, HES1, and JAG1 mRNA. Loss of Staufen1 induced TP63, SOX2, NOTCH1, HES1, and JAG1 mRNA expressions, which TINCR overexpression suppressed partially. In conclusion, TINCR is a novel regular of bronchial cell differentiation, affecting downstream regulators such as SOX2 and NOTCH genes, potentially in coordination with Staufen1.

Renal interstitial fibroblasts coproduce erythropoietin and renin under anaemic conditions

EBioMedicine

2021 Jan 25

Miyauchi, K;Nakai, T;Saito, S;Yamamoto, T;Sato, K;Kato, K;Nezu, M;Miyazaki, M;Ito, S;Yamamoto, M;Suzuki, N;
PMID: 33508746 | DOI: 10.1016/j.ebiom.2021.103209

Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown. We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure. Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin. Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.

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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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