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.

COVID-19 induces neuroinflammation and suppresses peroxisomes in the brain

Annals of neurology

2023 May 15

Roczkowsky, A;Limonta, D;Fernandes, JP;Branton, WG;Clarke, M;Hlavay, B;Noyce, RS;Joseph, JT;Ogando, NS;Das, SK;Elaish, M;Arbour, N;Evans, DH;Langdon, K;Hobman, TC;Power, C;
PMID: 37190821 | DOI: 10.1002/ana.26679

Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during SARS-CoV-2 infection using a multiplatform strategy.Brain tissues from COVID-19 (n=12) and other disease control (ODC) (n=12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS-CoV-2, were investigated by ddPCR, RT-qPCR and immunodetection methods.SARS-CoV-2 RNA was detected in the CNS of four patients with COVID-19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID-19 showed induction of pro-inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM-CSF and IL-18) compared to CNS tissues from ODC patients (p<0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11β and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID-19 patients compared to ODCs (p<0.05). SARS-CoV-2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post-infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post-infection (p<0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS-CoV-2 infected animals (p<0.05).COVID-19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS-CoV-2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post-acute sequelae of COVID-19. This article is protected by

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.

In situ sequence-specific visualization of single methylated cytosine on tissue sections using ICON probe and rolling-circle amplification

Histochemistry and cell biology

2022 Nov 23

Kitazawa, S;Haraguchi, R;Takaoka, Y;Kitazawa, R;
PMID: 36418613 | DOI: 10.1007/s00418-022-02165-2

Since epigenetic modifications differ from cell to cell, detecting the DNA methylation status of individual cells is requisite. Therefore, it is important to conduct "morphology-based epigenetics research", in which the sequence-specific DNA methylation status is observed while maintaining tissue architecture. Here we demonstrate a novel histochemical technique that efficiently shows the presence of a single methylated cytosine in a sequence-dependent manner by applying ICON (interstrand complexation with osmium for nucleic acids) probes. By optimizing the concentration and duration of potassium osmate treatment, ICON probes selectively hybridize to methylated cytosine on tissue sections. Since the elongation process by rolling-circle amplification through the padlock probe and synchronous amplification by the hyperbranching reaction at a constant temperature efficiently amplifies the reaction, it is possible to specifically detect the presence of a single methylated cytosine. Since the ICON probe is cross-linked to the nuclear or mitochondrial DNA of the target cell, subsequent elongation and multiplication reactions proceed like a tree growing in soil with its roots firmly planted, thus facilitating the demonstration of methylated cytosine in situ. Using this novel ICON-mediated histochemical method, detection of the methylation of DNA in the regulatory region of the RANK gene in cultured cells and of mitochondrial DNA in paraffin sections of mouse cerebellar tissue was achievable. This combined ICON and rolling-circle amplification method is the first that shows evidence of the presence of a single methylated cytosine in a sequence-specific manner in paraffin sections, and is foreseen as applicable to a wide range of epigenetic studies.

VP.59 A single-arm, open-label, multicenter study of tranilast for advanced heart failure in patients with muscular dystrophy

Neuromuscular Disorders

2022 Oct 01

Matsumura, T;Hashimoto, H;Sekimizu, M;Saito, A;Asakura, M;Kimura, K;Iwata, Y;
| DOI: 10.1016/j.nmd.2022.07.253

The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. Myocytes' damage induces TRPV2 expression on the sarcolemma, which causes calcium influx into the cytoplasm, and triggers degeneration. TRPV2 inhibition was effective in animal models of cardiomyopathy and muscular dystrophy (MD). Our pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Then, we planned a study to evaluate the safety and efficacy of tranilast for heart failure of MD patients. Subjects were MD patients whose serum BNP levels exceeded 100 pg/mL despite receiving standard therapy. Tranilast was administered orally at 100 mg thrice daily. The primary endpoint was the change in log (BNP) (⊿log [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous carvedilol study that resulted in a mean population ⊿log [BNP] of 0.18. TRPV2 expression on the mononuclear cell (MNC) surface, cardiac events, left ventricular fractional shortening (FS), human atrial natriuretic peptide (hANP), creatine kinase, and pinch strength were also assessed. Because of the poor general condition of many patients, among 18 patients included, 13 patients could be treated according to the protocol throughout the 6-month period. There were no serious adverse events related to tranilast except diarrhea, a known adverse effect. TRPV2 expression on the MNC surface was elevated at baseline and reduced after treatment. BNP, hANP, and FS remained stable. In the per-protocol set group, ⊿log [BNP] was -0.2 and significantly lower than that in the null hypothesis. In conclusion, tranilast is safe and effectively inhibits TRPV2 expression, even in MD patients with advanced heart failure. To evaluate the efficacy of tranilast in preventing heart failure, motor impairment, and respiratory failure, we are planning a study for mild MD patients.

A02 Altered epigenetic and transcriptional regulation during striatum-dependent memory in HD mice

A: Pathogenic mechanisms

2022 Sep 01

Alcalá-Vida, R;Lotz, C;Seguin, J;Decraene, C;Brulé, B;Awada, A;Bombardier, A;Cosquer, B;Pereira de Vasconcelos, A;Brouillet, E;Cassel, J;Boutillier, A;Merienne, K;
| DOI: 10.1136/jnnp-2022-ehdn.2

Epigenetic mechanisms are altered in the striatum of HD patients and mouse models, but how they might contribute to pathogenesis, including cognitive deficits, is unclear. Epigenetic regulation is critical to learning and memory processes, through transcriptional control of gene program promoting neural plasticity. We asked whether memory-associated epigenetic and transcriptional responses were impaired in HD R6/1 mice. To this end, we trained R6/1 mice (and control mice) in an aquatic navigation task, the double H maze, which allows assessing striatum-dependent memory (e.g. egocentric spatial memory). We then generated ChIP-seq, 4C-seq and RNA-seq datasets on striatal tissue of HD and control mice during egocentric memory processing, including memory acquisition and consolidation/recall. Egocentric memory was altered since early symptomatic stage in R6/1 mice, which correlated with dramatic reduction of striatal epigenetic and transcriptional changes induced by memory process. More specifically, multi-omic analysis showed that, during memory acquisition, 3D chromatin re-organization and transcriptional induction at BDNF-related genes were diminished in R6/1 striatum. Moreover, we found that changes in H3K9 acetylation (H3K9ac), which accompanied memory process in normal striatum, were attenuated in R6/1 striatum. Functional enrichment analyses further indicated that altered H3K9ac regulation during late phase of egocentric memory process (e.g. consolidation/recall) contributed to impaired TGFβ-dependent cellular plasticity. Together, this study provides support to the hypothesis that epigenetic dysregulation in HD contributes to cognitive deficits, and shed light on new targets of striatal plasticity, particularly H3K9ac and TFGβ signaling.

A01 Somatic mosaicism of the HTT cag repeat in intermediate allele carriers with neurocognitive symptoms compatible with huntington disease

A: Pathogenic mechanisms

2022 Sep 01

Ruiz de Sabando, A;Ciosi, M;Galbete, A;Monckton, D;Ramos-Arroyo, M;
| DOI: 10.1136/jnnp-2022-ehdn.1

We aimed to determine the possible role of CAG somatic expansions on the clinical expression of intermediate allele (IA) carriers of the HTT gene, responsible for Huntington disease (HD). We performed exon one sequencing analysis of the HTT gene on peripheral blood DNA in a Spanish cohort of asymptomatic IA carriers (n=55), symptomatic IA carriers (n=86) and HD subjects (n=124). Additionally, we investigated different brain regions of an individual carrying an HTT allele with 33 CAGs, with neurocognitive symptoms. Linear regression models were used to analyse the association between CAG length and age with somatic mosaicism. Symptomatic IA carriers presented with motor (80%), cognitive (20%) and/or behavioural (22%) signs, and an average age of onset of 58.7 years±18.6. Somatic mosaicism is CAG- and age-dependent in alleles of CAG≥27 CAGs, with b=0.04 (95% CI: 0.035-0.046), and b=0.001 (95% CI: 0.001-0.002), respectively, for all IAs. There was no statistical difference between HTT somatic mosaicism in symptomatic vs asymptomatic IA carriers (p=0.066). Somatic expansions of +1 and +2 CAGs were detected in the brain of the individual with 33 CAGs, with the highest expansion ratio observed in the putamen, where up to 10% of the DNA molecules underwent somatic expansion. In conclusion, somatic CAG expansions observed in blood cannot explain, overall, the neurocognitive signs of IA carriers. However, somatic instability occurs in IAs, which changes with CAG number and age; therefore, the presence of cells in the brain that express up to +2 CAGs may be important when considering the phenotypes of those alleles close to the pathological threshold.

Colocalization of Gene Expression and DNA Methylation with Genetic Risk Variants Supports Functional Roles of MUC5B and DSP in Idiopathic Pulmonary Fibrosis

American journal of respiratory and critical care medicine

2022 Jul 11

Borie, R;Cardwell, J;Konigsberg, IR;Moore, CM;Zhang, W;Sasse, SK;Gally, F;Dobrinskikh, E;Walts, A;Powers, J;Brancato, J;Rojas, M;Wolters, PJ;Brown, KK;Blackwell, TS;Nakanishi, T;Richards, JB;Gerber, AN;Fingerlin, TE;Sachs, N;Pulit, SL;Zappala, Z;Schwartz, DA;Yang, IV;
PMID: 35816432 | DOI: 10.1164/rccm.202110-2308OC

Common genetic variants have been associated with idiopathic pulmonary fibrosis (IPF).To determine functional relevance of the 10 IPF-associated common genetic variants we previously identified.We performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals and functional validation by luciferase reporter assays. Illumina MEGA genotyping arrays, mRNA sequencing, and Illumina 850k methylation arrays were performed on lung tissue of participants with IPF (234 RNA and 345 DNA samples) and non-diseased controls (188 RNA and 202 DNA samples).Focusing on genetic variants within 10 IPF-associated genetic loci, we identified 27 eQTLs in controls and 24 eQTLs in cases (false-discovery-rate-adjusted p<0.05). Among these signals, we identified associations of lead variants rs35705950 with expression of MUC5B and rs2076295 with expression of DSP in both cases and controls. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. We also demonstrated strong co-localization of eQTL/mQTL and genetic signal in MUC5B (rs35705950) and DSP (rs2076295). Functional validation of the mQTL in MUC5B using luciferase reporter assays demonstrates that the CpG resides within a putative internal repressor element.We have established a relationship of the common IPF genetic risk variants rs35705950 and rs2076295 with respective changes in MUC5B and DSP expression and methylation. These results provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.

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.

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

PP 6.2- 00106 CAR/CXCR5 T cells contact HIV vRNA+ cells in HIV-infected humanized DRAGA mice

Journal of Virus Eradication

2022 Dec 01

Pumtang-On, P;Sevcik, E;Davey, B;Goodarzi, N;Vezys, V;Casares, S;Rao, M;Skinner, P;
| DOI: 10.1016/j.jve.2022.100255

Background: HIV-specific chimeric antigen receptor T (CAR T) cells are being developed as a potential approach towards curing HIV infection. During infection, HIV replication is concentrated in B cell follicles, and viral reservoirs such as B cell follicles are a significant barrier to an HIV cure. We developed HIV-specific CAR T cells expressing the follicular homing receptor CXCR5 (CAR/CXCR5 T cells) to target follicular HIV reservoirs. We hypothesized after infusion of CAR/CXCR5 T cells in humanized HIV-infected DRAGA mice, CAR/CXCR5 T cells would accumulate in lymphoid follicles, make direct contact with HIV+ cells, lead to reductions in HIV viral loads, and preserve human CD4 T cells. Methods: Fourteen female humanized DRAGA mice were included in this study. Twelve mice were infected with 10 000 TCID50 of HIV-1 BaL. Levels of HIV-1 plasma viral loads and CD4 T cells were monitored using qRT-PCR and flow cytometry. Two spleens from uninfected mice were used to produce transduced CAR/CXCR5 T cells and transduced cell products (2×105 cells/gram) were infused in six HIV-infected mice. RNAscope combined with immunohistochemistry was used to visualize locations and quantities of CAR/CXCR5 T cells and HIV vRNA+ cells in lymphoid tissues. Results: All mice were HIV-1 detectable nbefore infusion of CAR/CXCR5 T cells. High levels of CAR/CXCR5 T cells and HIV vRNA+ cells were detected at 6 days post-infusion in lymphoid tissues. Many CAR/CXCR5 T cells were found in direct contact with HIV vRNA+ cells. However, many CAR/CXCR5 T cells, presumably CD4+ cells, were HIV vRNA+ and likely spreading infection. No differences in HIV plasma viral loads or CD4 T cell counts were observed between control and treated animals. Conclusions: These studies support the use of the HIV-infected DRAGA mouse model for HIV cure research studies. Using this model, we showed CAR/CXCR5 T cells accumulate in follicle-like structures with HIV vRNA+ cells and come in contact with vRNA+ cells. The simultaneous detection of CAR T cells with high levels of HIV vRNA+ cells indicates the need for HIV-resistant CAR T cells. These preliminary findings demonstrate the HIV-infected DRAGA mouse model is extremely valuable for evaluating HIV cure approaches.

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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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