Golgi localization of SARS-CoV-2 spike protein and interaction with furin in cerebral COVID-19 microangiopathy: a clue to the central nervous system involvement?

Free Neuropathology

2023 Jan 01

Boluda, S;Mokhtari, K;Megarbane, B;

In a neuropathological series of 20 COVID-19 cases, we analyzed six cases (three biopsies and three autopsies) with multiple foci predominantly affecting the white matter as shown by MRI. The cases presented with microhemorrhages evocative of small artery diseases. This COVID-19 associated cerebral microangiopathy (CCM) was characterized by perivascular changes: arterioles were surrounded by vacuolized tissue, clustered macrophages, large axonal swellings and a crown arrangement of aquaporin-4 immunoreactivity. There was evidence of blood-brain-barrier leakage. Fibrinoid necrosis, vascular occlusion, perivascular cuffing and demyelination were absent. While no viral particle or viral RNA was found in the brain, the SARS-CoV-2 spike protein was detected in the Golgi apparatus of brain endothelial cells where it closely associated with furin, a host protease known to play a key role in virus replication. Endothelial cells in culture were not permissive to SARS-CoV-2 replication. The distribution of the spike protein in brain endothelial cells differed from that observed in pneumocytes. In the latter, the diffuse cytoplasmic labeling suggested a complete replication cycle with viral release, notably through the lysosomal pathway. In contrast, in cerebral endothelial cells the excretion cycle was blocked in the Golgi apparatus. Interruption of the excretion cycle could explain the difficulty of SARS-CoV-2 to infect endothelial cells _in vitro_ and to produce viral RNA in the brain. Specific metabolism of the virus in brain endothelial cells could weaken the cell walls and eventually lead to the characteristic lesions of COVID-19 associated cerebral microangiopathy. Furin as a modulator of vascular permeability could provide some clues for the control of late effects of microangiopathy.

WNT16 is Robustly Increased by Oncostatin M in Mouse Calvarial Osteoblasts and Acts as a Negative Feedback Regulator of Osteoclast Formation Induced by Oncostatin M

Journal of inflammation research

2021 Sep 18

Henning, P;Movérare-Skrtic, S;Westerlund, A;Chaves de Souza, PP;Floriano-Marcelino, T;Nilsson, KH;El Shahawy, M;Ohlsson, C;Lerner, UH;
PMID: 34566421 | DOI: 10.2147/JIR.S323435

Bone loss is often observed adjacent to inflammatory processes. The WNT signaling pathways have been implicated as novel regulators of both immune responses and bone metabolism. WNT16 is important for cortical bone mass by inhibiting osteoclast differentiation, and we have here investigated the regulation of WNT16 by several members of the pro-inflammatory gp130 cytokine family.The expression and regulation of Wnt16 in primary murine cells were studied by qPCR, scRNAseq and in situ hybridization. Signaling pathways were studied by siRNA silencing. The importance of oncostatin M (OSM)-induced WNT16 expression for osteoclastogenesis was studied in cells from Wnt16-deficient and wild-type mice.We found that IL-6/sIL-6R and OSM induce the expression of Wnt16 in primary mouse calvarial osteoblasts, with OSM being the most robust stimulator. The induction of Wnt16 by OSM was dependent on gp130 and OSM receptor (OSMR), and downstream signaling by the SHC1/STAT3 pathway, but independent of ERK. Stimulation of the calvarial cells with OSM resulted in enhanced numbers of mature, oversized osteoclasts when cells were isolated from Wnt16 deficient mice compared to cells from wild-type mice. OSM did not affect Wnt16 mRNA expression in bone marrow cell cultures, explained by the finding that Wnt16 and Osmr are expressed in distinctly different cells in bone marrow, nor was osteoclast differentiation different in OSM-stimulated bone marrow cell cultures isolated from Wnt16-/- or wild-type mice. Furthermore, we found that Wnt16 expression is substantially lower in cells from bone marrow compared to calvarial osteoblasts.These findings demonstrate that OSM is a robust stimulator of Wnt16 mRNA in calvarial osteoblasts and that WNT16 acts as a negative feedback regulator of OSM-induced osteoclast formation in the calvarial bone cells, but not in the bone marrow.

Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cells differentiation

American journal of human genetics

2022 Apr 04

Coolen, M;Altin, N;Rajamani, K;Pereira, E;Siquier-Pernet, K;Puig Lombardi, E;Moreno, N;Barcia, G;Yvert, M;Laquerrière, A;Pouliet, A;Nitschké, P;Boddaert, N;Rausell, A;Razavi, F;Afenjar, A;Billette de Villemeur, T;Al-Maawali, A;Al-Thihli, K;Baptista, J;Beleza-Meireles, A;Garel, C;Legendre, M;Gelot, A;Burglen, L;Moutton, S;Cantagrel, V;
PMID: 35390279 | DOI: 10.1016/j.ajhg.2022.03.010

Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.

Motoneuronal inflammasome activation triggers excessive neuroinflammation and impedes regeneration after sciatic nerve injury

Journal of neuroinflammation

2022 Mar 19

Molnár, K;Nógrádi, B;Kristóf, R;Mészáros, Á;Pajer, K;Siklós, L;Nógrádi, A;Wilhelm, I;Krizbai, IA;
PMID: 35305649 | DOI: 10.1186/s12974-022-02427-9

Peripheral nerve injuries are accompanied by inflammatory reactions, over-activation of which may hinder recovery. Among pro-inflammatory pathways, inflammasomes are one of the most potent, leading to release of active IL-1β. Our aim was to understand how inflammasomes participate in central inflammatory reactions accompanying peripheral nerve injury.After axotomy of the sciatic nerve, priming and activation of the NLRP3 inflammasome was examined in cells of the spinal cord. Regeneration of the nerve was evaluated after coaptation using sciatic functional index measurements and retrograde tracing.In the first 3 days after the injury, elements of the NLRP3 inflammasome were markedly upregulated in the L4-L5 segments of the spinal cord, followed by assembly of the inflammasome and secretion of active IL-1β. Although glial cells are traditionally viewed as initiators of neuroinflammation, in this acute phase of inflammation, inflammasome activation was found exclusively in affected motoneurons of the ventral horn in our model. This process was significantly inhibited by 5-BDBD, a P2X4 receptor inhibitor and MCC950, a potent NLRP3 inhibitor. Although at later time points the NLRP3 protein was upregulated in microglia too, no signs of inflammasome activation were detected in these cells. Inhibition of inflammasome activation in motoneurons in the first days after nerve injury hindered development of microgliosis in the spinal cord. Moreover, P2X4 or inflammasome inhibition in the acute phase significantly enhanced nerve regeneration on both the morphological and the functional levels.Our results indicate that the central reaction initiated by sciatic nerve injury starts with inflammasome activation in motoneurons of the ventral horn, which triggers a complex inflammatory reaction and activation of microglia. Inhibition of neuronal inflammasome activation not only leads to a significant reduction of microgliosis, but has a beneficial effect on the recovery as well.

Mucosal and faecal neutrophil gelatinase-associated lipocalin as potential biomarkers for collagenous colitis

Journal of gastroenterology

2021 Aug 19

Bakke, I;Walaas, GA;Bruland, T;Røyset, ES;van Beelen Granlund, A;Escudero-Hernández, C;Thorsvik, S;Münch, A;Sandvik, AK;Østvik, AE;
PMID: 34414506 | DOI: 10.1007/s00535-021-01814-y

Collagenous colitis (CC) is an inflammatory bowel disease where chronic diarrhoea is the main symptom. Diagnostic markers distinguishing between CC and other causes of chronic diarrhoea remain elusive. This study explores neutrophil gelatinase-associated lipocalin (NGAL) and its mRNA lipocalin2 (LCN2) as histological and faecal disease markers in CC.NGAL/LCN2 were studied in colonic biopsies from CC patients before and during budesonide treatment using RNA sequencing (n = 9/group), in situ hybridization (ISH) (n = 13-22/group) and immunohistochemistry (IHC) (n = 14-25/group). Faecal samples from CC (n = 3-28/group), irritable bowel syndrome diarrhoea (IBS-D) (n = 14) and healthy controls (HC) (n = 15) were assayed for NGAL and calprotectin.NGAL/LCN2 protein and mRNA expression were upregulated in active CC vs HC, and vs paired samples of treated CC in clinical remission. IHC and ISH localized increased NGAL/LCN2 mainly to epithelium of active CC, compared to almost absence in HC and treated CC. In contrast, calprotectin was solely expressed in immune cells. Despite great individual differences, faecal NGAL was significantly increased in active CC compared to HC, IBS-D and treated CC and had high test sensitivity. Faecal calprotectin levels were variably increased in active CC, but the values remained below usual clinical cut-offs.NGAL/LCN2 is upregulated in the epithelium of active CC and reduced during budesonide-induced clinical remission to the level of HC and IBD-S. This was reflected in NGAL faecal concentrations. We propose NGAL as an IHC marker for disease activity in CC and a potential faecal biomarker discriminating CC from HC and IBS-D.

Dengue and Zika Virus Cross-Reactive Human Monoclonal Antibodies Protect against Spondweni Virus Infection and Pathogenesis in Mice.

Cell Rep.

2019 Feb 05

Salazar V, Jagger BW, Mongkolsapaya J, Burgomaster KE, Dejnirattisai W, Winkler ES, Fernandez E, Nelson CA, Fremont DH, Pierson TC, Crowe JE Jr, Screaton GR, Diamond MS.
PMID: 30726740 | DOI: 10.1016/j.celrep.2019.01.052

Spondweni virus (SPOV) is the flavivirus that is most closely related to Zika virus (ZIKV). Although SPOV causes sporadic human infections in Africa, recently it was found in Culex mosquitoes in Haiti. To investigate the pathogenic spectrum of SPOV, we developed infection models in mice. Although two SPOV strains failed to cause disease in immunocompetent mice, each accumulated in the brain, spleen, eye, testis, and kidney when type I interferon signaling was blocked and unexpectedly caused infection, immune cell infiltration, and swelling in the ankle. In pregnant mice, SPOV replicated in the placenta and fetus but did not cause placental insufficiency or microcephaly. We identified human antibodies from ZIKV or DENV immune subjects that neutralized SPOV infection and protected against lethal challenge. Our experiments describe similarities and differences in clinical syndromes between SPOV and ZIKV and suggest that their serological relatedness has implications for antibody therapeutics and flavivirus vaccine development.

Role of IQGAP1 in Papillomavirus-Associated Head and Neck Tumorigenesis

Cancers

2021 May 10

Wei, T;Choi, S;Buehler, D;Lee, D;Ward-Shaw, E;Anderson, RA;Lambert, PF;
PMID: 34068608 | DOI: 10.3390/cancers13092276

Approximately 25% of head and neck squamous cell carcinomas (HNSCC) are associated with human papillomavirus (HPV) infection. In these cancers as well as in HPV-associated anogenital cancers, PI3K signaling is highly activated. We previously showed that IQ motif-containing GTPase activating protein 1 (IQGAP1), a PI3K pathway scaffolding protein, is overexpressed in and contributes to HNSCC and that blocking IQGAP1-mediated PI3K signaling reduces HPV-positive HNSCC cell survival and migration. In this study, we tested whether IQGAP1 promotes papillomavirus (PV)-associated HNSCCs. IQGAP1 was necessary for optimal PI3K signaling induced by HPV16 oncoproteins in transgenic mice and MmuPV1 infection, a mouse papillomavirus that causes HNSCC in mice. Furthermore, we found that, at 6 months post-infection, MmuPV1-infected Iqgap1-/- mice developed significantly less severe tumor phenotypes than MmuPV1-infected Iqgap1+/+ mice, indicating a role of IQGAP1 in MmuPV1-associated HNSCC. The tumors resulting from MmuPV1 infection showed features consistent with HPV infection and HPV-associated cancer. However, such IQGAP1-dependent effects on disease severity were not observed in an HPV16 transgenic mouse model for HNC. This may reflect that IQGAP1 plays a role in earlier stages of viral pathogenesis, or other activities of HPV16 oncogenes are more dominant in driving carcinogenesis than their influence on PI3K signaling.

SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions

The Journal of clinical investigation

2023 May 11

Pilat, JM;Brown, RE;Chen, Z;Berle, NJ;Othon, AP;Washington, M;Anant, SA;Kurokawa, S;Ng, VH;Thompson, JJ;Jacobse, J;Goettel, JA;Lee, E;Choksi, YA;Lau, KS;Short, SP;Williams, CS;
PMID: 37166989 | DOI: 10.1172/JCI165988

Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP's contributions to sporadic colorectal carcinogenesis. In human scRNA-seq datasets, we discovered that SELENOP expression rises as normal colon stem cells transform into adenomas that progress into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involves conditional, intestinal epithelial-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as CRC and noncancer cell lines. Selenop KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining SELENOP's mechanism of action, we mapped protein-protein interactions between SELENOP and the WNT co-receptor low-density lipoprotein receptor-related protein 5/6 (LRP5/6). Lastly, we confirmed that SELENOP:LRP5/6 interactions contributed to SELENOP's effects on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.

LINC00892 Is an lncRNA Induced by T Cell Activation and Expressed by Follicular Lymphoma-Resident T Helper Cells

Non-Coding RNA

2022 Jun 01

Iaccarino, I;Mourtada, F;Reinke, S;Patil, P;Doose, G;Monaco, G;Hoffmann, S;Siebert, R;Klapper, W;
| DOI: 10.3390/ncrna8030040

Successful immunotherapy in both solid tumors and in hematological malignancies relies on the ability of T lymphocytes to infiltrate the cancer tissue and mount an immune response against the tumor. Biomarkers able to discern the amount and the types of T lymphocytes infiltrating a given tumor therefore have high diagnostic and prognostic value. Given that lncRNAs are known to have a highly cell-type-specific expression pattern, we searched for lncRNAs specifically expressed by activated T cells and at the same time in a kind of lymphoma, follicular lymphoma, where the microenvironment is known to play a critical role in the regulation of antitumor immunity. We focused on a non-coding transcript, annotated as LINC00892, which reaches extremely high expression levels following cell activation in Jurkat cells. Interestingly LINC00892 has an expression pattern resembling that of genes involved in T cell memory. Accordingly, LINC00892 is mostly expressed by the effector memory and helper CD4+ T cell sub-types but not by naïve T cells. In situ analyses of LINC00892 expression in normal lymph nodes and in follicular lymphoma biopsies show that its expression is limited to CD4+ PD1hi T cells, with a subcellular localization within the germinal center matching that of follicular helper T cells. Our analysis therefore suggests that the previously uncharacterized lncRNA LINC00892 could be a useful biomarker for the detection of CD4+ memory T cells in both normal and tumor tissues.

PAC1R Genotype to Phenotype Correlations in Autism Spectrum Disorder.

Autism Res. 2018 Dec 17.

2018 Dec 17

Goodrich M, Armour AC, Panchapakesan K, You X, Devaney J, Knoblach S, Sullivan CAW, Herrero MJ, Gupta AR, Vaidya CJ, Kenworthy L, Corbin JG.
PMID: 30556326 | DOI: 10.1002/aur.2051

Amygdala dysfunction has been implicated in numerous neurodevelopmental disorders, including autism spectrum disorder (ASD). Previous studies in mice and humans, respectively, have linked Pac1r/PAC1R function to social behavior and PTSD-susceptibility. Based on this connection to social and emotional processing and the central role played by the amygdala in ASD, we examined a putative role for PAC1R in social deficits in ASD and determined the pattern of gene expression in the developing mouse and human amygdala. We reveal that Pac1r/PAC1R is expressed in both mouse and human amygdala from mid-neurogenesis through early postnatal stages, critical time points when altered brain trajectories are hypothesized to unfold in ASD. We further find that parents of autistic children carrying a previously identified PTSD-risk genotype (CC) report greater reciprocal social deficits compared to those carrying the non-risk GC genotype. Additionally, by exploring resting-state functional connectivity differences in a subsample of the larger behavioral sample, we find higher functional connectivity between the amygdala and right middle temporal gyrus in individuals with the CC risk genotype. Thus, using multimodal approaches, our data reveal that the amygdala-expressed PAC1R gene may be linked to severity of ASD social phenotype and possible alterations in brain connectivity, therefore potentially acting as a modifier of amygdala-related phenotypes. Autism Res 2018. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this multimodal study across mouse and human, we examined expression patterns of Pac1r/PAC1R, a gene implicated in social behavior, and further explored whether a previously identified human PTSD-linked mutation in PAC1R can predict brain connectivity and social deficits in ASD. We find that PAC1R is highly expressed in the both the mouse and human amygdala. Furthermore, our human data suggest that PAC1R genotype is linked to severity of social deficits and functional amygdala connectivity in ASD.

Hedgehog Signaling Modulates Interleukin‐33‐Dependent Extrahepatic Bile Duct Cell Proliferation in Mice.

Hepatol Commun. (2018)

2018 Dec 11

Razumilava N, Shiota J, Mohamad Zaki NH, Ocadiz-Ruiz R, Cieslak CM, Zakharia K, Allen BL, Gores GJ, Samuelson LC, Merchant JL.
| DOI: 10.1002/hep4.1295

Hedgehog (HH) signaling participates in hepatobiliary repair after injury and is activated in patients with cholangiopathies. Cholangiopathies are associated with bile duct (BD) hyperplasia, including expansion of peribiliary glands, the niche for biliary progenitor cells. The inflammation‐associated cytokine interleukin (IL)‐33 is also up‐regulated in cholangiopathies, including cholangiocarcinoma. We hypothesized that HH signaling synergizes with IL‐33 in acute inflammation‐induced BD hyperplasia. We measured extrahepatic BD (EHBD) thickness and cell proliferation with and without an IL‐33 challenge in wild‐type mice, mice overexpressing Sonic HH (pCMV‐Shh), and mice with loss of the HH pathway effector glioma‐associated oncogene 1 (Gli1lacZ/lacZ). LacZ reporter mice were used to map the expression of HH effector genes in mouse EHBDs. An EHBD organoid (BDO) system was developed to study biliary progenitor cells in vitro. EHBDs from the HH overexpressing pCMV‐Shh mice showed increased epithelial cell proliferation and hyperplasia when challenged with IL‐33. In Gli1lacZ/lacZ mice, we observed a decreased proliferative response to IL‐33 and decreased expression of Il6. The HH ligands Shh and Indian HH (Ihh) were expressed in epithelial cells, whereas the transcriptional effectors Gli1, Gli2, and Gli3 and the HH receptor Patched1 (Ptch1) were expressed in stromal cells, as assessed by in situ hybridization and lacZ reporter mice. Although BDO cells lacked canonical HH signaling, they expressed the IL‐33 receptor suppression of tumorigenicity 2. Accordingly, IL‐33 treatment directly induced BDO cell proliferation in a nuclear factor κB‐dependent manner. Conclusion: HH ligand overexpression enhances EHBD epithelial cell proliferation induced by IL‐33. This proproliferative synergism of HH and IL‐33 involves crosstalk between HH ligand‐producing epithelial cells and HH‐responding stromal cells.

p53-targeted lincRNA-p21 acts as a tumor suppressor by inhibiting JAK2/STAT3 signaling pathways in head and neck squamous cell carcinoma

Mol Cancer

2019 Mar 11

Jin S, Yang X, Li J, Yang W, Ma H and Zhang Z
PMID: 30857539 | DOI: 10.1186/s12943-019-0993-3

BACKGROUND: Long intergenic noncoding RNA p21 (lincRNA-p21) is considered a target of wild-type p53, but little is known about its regulation by mutant p53 and its functions during the progression of head and neck squamous cell carcinoma (HNSCC). METHODS: RNAscope was used to detect the expression and distribution of lincRNA-p21. Chromatin immunoprecipitation and electrophoretic mobility shift assays were performed to analyze the transcriptional regulation of lincRNA-p21 in HNSCC cells. The biological functions of lincRNA-p21 were investigated in vitro and in vivo. RNA immunoprecipitation and pull-down assays were used to detect the direct binding of lincRNA-p21. RESULTS: Lower lincRNA-p21 expression was observed in HNSCC tissues and indicated worse prognosis. Both wild and mutant type p53 transcriptionally regulated lincRNA-p21, but nuclear transcription factor Y subunit alpha (NF-YA) was essential for mutant p53 in the regulation of lincRNA-p21. Ectopic expression of lincRNA-p21 significantly inhibited cell proliferation capacity in vitro and in vivo and vice versa. Moreover, the overexpression of lincRNA-p21 induced G1 arrest and apoptosis. Knockdown NF-YA expression reversed tumor suppressor activation of lincRNA-p21 in mutant p53 cells, not wild-type p53 cells. A negative correlation was observed between lincRNA-p21 and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in HNSCC tissues. High lincRNA-p21 expression inhibited Janus kinase 2 (JAK2)/STAT3 signal activation and vice versa. Further, we observed direct binding to STAT3 by lincRNA-p21 in HNSCC cells, which suppressed STAT3-induced oncogenic potential. CONCLUSIONS: Our results revealed the transcriptional regulation of lincRNA-p21 by the mutant p53/NF-YA complex in HNSCC. LincRNA-p21 acted as a tumor suppressor in HNSCC progression, which was attributed to direct binding to STAT3 and blocking of JAK2/STAT3 signaling.

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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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