A High-Fat Diet Activates the BAs-FXR Axis and Triggers Cancer-Associated Fibroblast Properties in the Colon

Cellular and molecular gastroenterology and hepatology

2021 Dec 29

Kim, TY;Kim, S;Kim, Y;Lee, YS;Lee, S;Lee, SH;Kweon, MN;
PMID: 34971821 | DOI: 10.1016/j.jcmgh.2021.12.015

Dietary signals are known to modulate stemness and tumorigenicity of intestinal progenitors; however, the impact of a high-fat diet (HFD) on the intestinal stem cell (ISC) niche and its association with colorectal cancer remains unclear. Thus, we aimed to investigate how a HFD affects the ISC niche and its regulatory factors.Mice were fed a purified diet (PD) or HFD for 2 months. The expression levels of ISC-related markers, ISC-supportive signals, and Wnt2b were assessed with real-time quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence staining. RNA sequencing and metabolic function were analyzed in mesenchymal stromal cells (MSCs) from PD- and HFD-fed mice. Fecal microbiota were analyzed by 16s rRNA sequencing. Bile salt hydrolase activity and bile acid (BA) levels were measured.We found that expression of CD44 and Wnt signal-related genes was higher in the colonic crypts of HFD-fed mice than in those fed a PD. Within the ISC niche, MSCs were expanded and secreted predominant levels of Wnt2b in the colon of HFD-fed mice. Of note, increased energy metabolism and cancer-associated fibroblast (CAF)-like properties were found in the colonic MSCs of HFD-fed mice. Moreover, colonic MSCs from HFD-fed mice promoted the growth of tumorigenic properties and accelerated the expression of cancer stem cell (CSC)-related markers in colon organoids. In particular, production of primary and secondary BAs was increased through the expansion of bile salt hydrolase-encoding bacteria in HFD-fed mice. Most importantly, BAs-FXR interaction stimulated Wnt2b production in colonic CAF-like MSCs.HFD-induced colonic CAF-like MSCs play an indispensable role in balancing the properties of CSCs through activation of the BAs-FXR axis.

Persistence of Lgr5+ colonic epithelial stem cells in mouse models of inflammatory bowel disease

American journal of physiology. Gastrointestinal and liver physiology

2021 Jul 14

Girish, N;Liu, CY;Gadeock, S;Gomez, ML;Huang, Y;Sharifkhodaei, Z;Washington, MK;Polk, DB;
PMID: 34260310 | DOI: 10.1152/ajpgi.00248.2020

Intestinal mucosal healing is the primary therapeutic goal of medical treatments for inflammatory bowel disease (IBD). Epithelial stem cells are key players in the healing process. Lgr5+ stem cells maintain cellular turnover during homeostasis in the colonic crypt. However, they are lost and dispensable for repair in a wide variety of injury models, including dextran sulfate sodium (DSS) colitis, radiation, helminth infection, and T-cell activation. The direct loss of Lgr5+ cells activates a plasticity response in the epithelium in which other cell types can serve as stem cells. Whether this paradigm applies to mouse models of IBD remains unknown. In contrast to previously tested models, IBD models involve an inflammatory response rooted in the loss of immunologic tolerance to intestinal luminal contents including the microbiome. Here we show the persistence of Lgr5+ cells in oxazolone, TNBS, and Il10-/- and Il10-/- Tnfr1-/- IBD models. This contrasts with results obtained from DSS-induced injury. Through high-throughput expression profiling, we find that these colitis models were associated with distinct patterns of cytokine expression. Direct exposure of colonic epithelial organoids to DSS, oxazolone, or TNBS resulted in increased apoptosis and loss of Lgr5+ cells. Targeted ablation of Lgr5+ cells resulted in severe exacerbation of chronic, antibody-induced IL-10-deficient colitis, but had only modest effects in TNBS-induced colitis. These results show that distinct mouse models of IBD-like colitis induce different patterns of Lgr5+ stem cell retention and function.

Increased angiotensin II formation in the brain modulates cardiovascular homeostasis and erythropoiesis

Clinical science (London, England : 1979)

2021 Jun 11

Rodrigues, AF;Todiras, M;Qadri, F;Campagnole-Santos, MJ;Alenina, N;Bader, M;
PMID: 34013320 | DOI: 10.1042/CS20210072

In spite of the fact that the modulatory effects of angiotensin II (Ang II) on the sympathetic nerve activity to targeted organs involved in blood pressure (BP) regulation is well acknowledged, the local production of this peptide in the brain and the consequences of enhanced central Ang II beyond the cardiovascular system are not yet well comprehended. In the present study, we generated and validated a new transgenic mouse line overexpressing the rat full-length angiotensinogen (Agt) protein specifically in the brain (Agt-Tg). Adult Agt-Tg mice presented overall increased gene expression of total Agt in the brain including brainstem and hypothalamus. In addition, the excess of Agt led to abundantly detectable brain Ang II levels as well as increased circulating copeptin levels. Agt-Tg displayed raised BP in acute recordings, while long-term telemetrically measured basal BP was indistinguishable from wild-types. Agt-Tg has altered peripheral renin-angiotensin system and vasomotor sympathetic tone homeostasis because renal gene expression analysis, plasma Ang II measurements and ganglionic blockade experiments revealed suppressed renin expression and reduced Ang II and higher neurogenic pressure response, respectively. Plasma and urine screens revealed apparently normal fluid and electrolyte handling in Agt-Tg. Interestingly, hematological analyses showed increased hematocrit in Agt-Tg caused by enhanced erythropoiesis, which was reverted by submitting the transgenic mice to a long-term peripheral sympathectomy protocol. Collectively, our findings suggest that Agt-Tg is a valuable tool to study not only brain Ang II formation and its modulatory effects on cardiovascular homeostasis but also its role in erythropoiesis control via autonomic modulation.

Prefrontal cortex PACAP signaling: organization and role in stress regulation

Stress (Amsterdam, Netherlands)

2021 Mar 01

Martelle, SE;Cotella, EM;Nawreen, N;Chen, C;Packard, BA;Fitzgerald, M;Herman, JP;
PMID: 33726625 | DOI: 10.1080/10253890.2021.1887849

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuromodulatory peptide strongly implicated in nervous stress processing. Human polymorphism of the primary PACAP receptor (PAC1) is linked to psychiatric disorders, including posttraumatic stress disorder (PTSD). Prefrontal cortex PACAP signaling is associated with processing of traumatic stress and fear learning, suggesting a potential role in PTSD-related deficits. We used RNAscope to define the cellular location of PACAP and PAC1 in the infralimbic cortex (IL). Subsequent experiments used a pharmacological approach to assess the impact of IL PACAP infusion on behavioral and physiological stress response and fear memory. Adult male Sprague-Dawley rats were bilaterally microinjected with PACAP (1 ug) or vehicle into the IL, 30 minutes prior to forced swim test (FST). Blood was sampled at 15, 30, 60, and 120 minutes for analysis of hypothalamic pituitary adrenal (HPA) axis reactivity. Five days after, animals were tested in a 3-day passive avoidance paradigm with subsequent testing of fear retention two weeks later. We observed that PACAP is highly expressed in putative pyramidal neurons (identified by VGlut1 expression), while PAC1 is enriched in interneurons (identified by GAD). Pretreatment with PACAP increased active coping style in the FST, despite higher levels of ACTH and corticosterone. The treatment was also sufficient to cause an increase in anxiety-like behavior in a dark/light crossover test and enhanced retention of passive avoidance. Our data suggest that IL PACAP plays a role in driving stress responses and in processing of fear memories, likely mediated by inhibition of cortical drive.

Localization of Angiotensin II Type 1 receptor gene expression in rodent and human kidneys

American journal of physiology. Renal physiology

2021 Feb 22

Schrankl, J;Fuchs, M;Broeker, K;Daniel, C;Kurtz, A;Wagner, C;
PMID: 33615887 | DOI: 10.1152/ajprenal.00550.2020

The kidneys are an important target for angiotensin II (ANG II). In the adult kidneys the effects of ANG II are mediated mainly by ANG II type 1 (AT1) receptors. AT1 receptor expression has been reported for a variety of different cell types within the kidneys, suggesting a broad spectrum of actions for ANG II. Since there have been heterogeneous results in the literature regarding the intrarenal distribution of AT1 receptors, this study aimed to obtain a comprehensive overview about the localization of AT1 receptor expression in mouse, rat and human kidneys. Using the cell specific and high-resolution RNAscope technique, we performed colocalization studies with various cell markers to specifically discriminate between different segments of the tubular and vascular system. Overall we found a similar pattern of AT1 mRNA expression in mouse, rat and human kidneys. AT1 receptors were detected in mesangial cells and renin-producing cells. In addition, AT1 mRNA was found in interstitial cells of the cortex and outer medulla. In rodents, late afferent and early efferent arterioles expressed AT1 receptor mRNA, but larger vessels of the investigated species showed no AT1 expression. Tubular expression of AT1 mRNA was species-dependent with a strong expression in proximal tubules of mice while expression was undetectable in human tubular cells. These findings suggest that the (juxta)glomerular area and the tubulointerstitium are conserved expression sites for AT1 receptors across species and might present the main target sites for ANG II in adult human and rodent kidneys.

A distinct repertoire of cancer-associated fibroblasts is enriched in cribriform prostate cancer

The journal of pathology. Clinical research

2021 Feb 18

Hesterberg, AB;Rios, BL;Wolf, EM;Tubbs, C;Wong, HY;Schaffer, KR;Lotan, TL;Giannico, GA;Gordetsky, JB;Hurley, PJ;
PMID: 33600062 | DOI: 10.1002/cjp2.205

Outcomes for men with localized prostate cancer vary widely, with some men effectively managed without treatment on active surveillance, while other men rapidly progress to metastatic disease despite curative-intent therapies. One of the strongest prognostic indicators of outcome is grade groups based on the Gleason grading system. Gleason grade 4 prostate cancer with cribriform morphology is associated with adverse outcomes and can be utilized clinically to improve risk stratification. The underpinnings of disease aggressiveness associated with cribriform architecture are not fully understood. Most studies have focused on genetic and molecular alterations in cribriform tumor cells; however, less is known about the tumor microenvironment in cribriform prostate cancer. Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts in the tumor microenvironment that impact cancer aggressiveness. The overall goal of this study was to determine if cribriform prostate cancers are associated with a unique repertoire of CAFs. Radical prostatectomy whole-tissue sections were analyzed for the expression of fibroblast markers (ASPN in combination with FAP, THY1, ENG, NT5E, TNC, and PDGFRβ) in stroma adjacent to benign glands and in Gleason grade 3, Gleason grade 4 cribriform, and Gleason grade 4 noncribriform prostate cancer by RNAscope . Halo Software was used to quantify percent positive stromal cells and expression per positive cell. The fibroblast subtypes enriched in prostate cancer were highly heterogeneous. Both overlapping and distinct populations of low abundant fibroblast subtypes in benign prostate stroma were enriched in Gleason grade 4 prostate cancer with cribriform morphology compared to Gleason grade 4 prostate cancer with noncribriform morphology and Gleason grade 3 prostate cancer. In addition, gene expression was distinctly altered in CAF subtypes adjacent to cribriform prostate cancer. Overall, these studies suggest that cribriform prostate cancer has a unique tumor microenvironment that may distinguish it from other Gleason grade 4 morphologies and lower Gleason grades.

Unlocking the Role of a Genital Herpesvirus, Otarine Herpesvirus 1, in California Sea Lion Cervical Cancer

Animals

2021 Feb 13

Deming, A;Wellehan, J;Colegrove, K;Hall, A;Luff, J;Lowenstine, L;Duignan, P;Cortés-Hinojosa, G;Gulland, F;
| DOI: 10.3390/ani11020491

Urogenital carcinoma in California sea lions (Zalophus californianus) is the most common cancer of marine mammals. Primary tumors occur in the cervix, vagina, penis, or prepuce and aggressively metastasize resulting in death. This cancer has been strongly associated with a sexually transmitted herpesvirus, otarine herpesvirus 1 (OtHV1), but the virus has been detected in genital tracts of sea lions without cancer and a causative link has not been established. To determine if OtHV1 has a role in causing urogenital carcinoma we sequenced the viral genome, quantified viral load from cervical tissue from sea lions with (n = 95) and without (n = 163) urogenital carcinoma, and measured viral mRNA expression using in situ mRNA hybridization (Basescope ) to quantify and identify the location of OtHV1 mRNA expression. Of the 95 sea lions diagnosed with urogenital carcinoma, 100% were qPCR positive for OtHV1, and 36% of the sea lions with a normal cervix were positive for the virus. The non-cancer OtHV1 positive cases had significantly lower viral loads in their cervix compared to the cervices from sea lions with urogenital carcinoma. The OtHV1 genome had several genes similar to the known oncogenes, and RNA in situ hybridization demonstrated high OtHV1 mRNA expression within the carcinoma lesions but not in normal cervical epithelium. The high viral loads, high mRNA expression of OtHV1 in the cervical tumors, and the presence of suspected OtHV1 oncogenes support the hypothesis that OtHV1 plays a significant role in the development of sea lion urogenital carcinoma.

Increased Abundance of Tumour-Associated Neutrophils in HPV-Negative Compared to HPV-Positive Oropharyngeal Squamous Cell Carcinoma Is Mediated by IL-1R Signalling

Frontiers in Oral Health

2021 Feb 11

Al-Sahaf, S;Hendawi, N;Ollington, B;Bolt, R;Ottewell, P;Hunter, K;Murdoch, C;
| DOI: 10.3389/froh.2021.604565

The incidence of human papillomavirus (HPV)-associated cancer is increasing and HPV is now implicated in the aetiology of more than 60% of all oropharyngeal squamous cell carcinomas (OPSCC). In OPSCC, innate immune cells such as neutrophils and macrophages generally correlate with poor prognosis, whilst adaptive immune cells, such as lymphocytes, tend to correlate with improved prognosis. This may, in part, be due to differences in the immune response within the tumour microenvironment leading to the recruitment of specific tumour-associated leukocyte sub-populations. In this study, we aimed to examine if differences exist in the levels of infiltrated leukocyte sub-populations, with particular emphasis on tumour-associated neutrophils (TAN), and to determine the mechanism of chemokine-induced leukocyte recruitment in HPV-positive compared to HPV-negative OPSCC. Immunohistochemical analysis showed that HPV-negative OPSCC contained significantly more neutrophils than HPV-positive tumours, whilst levels of CD68+ macrophages and CD3+ lymphocytes were similar. Using a 3D tissue culture model to represent tumour-stromal interactions, we demonstrated that HPV-negative tumour-stromal co-cultures expressed significantly higher levels of CXCL8, leading to increased neutrophil recruitment compared to their HPV-positive counterparts. HPV-negative OPSCC cells have previously been shown to express higher levels of IL-1 than their HPV-positive counterparts, indicating that this cytokine may be responsible for driving increased chemokine production in the HPV-negative 3D model. Inhibition of IL-1R in the tumour-stromal models using the receptor-specific antagonist, anakinra, dramatically reduced chemokine secretion and significantly impaired neutrophil and monocyte recruitment, suggesting that this tumour-stromal response is mediated by the IL-1/IL-1R axis. Here, we identify a mechanism by which HPV-negative OPSCC may recruit more TAN than HPV-positive OPSCC. Since TAN are associated with poor prognosis in OPSCC, our study identifies potential therapeutic targets aimed at redressing the chemokine imbalance to reduce innate immune cell infiltration with the aim of improving patient outcome.

A Modeling Framework for Investigating the Role of Human Atrial Fibroblast Calcium Signaling in Fibrogenesis

Biophysical Journal

2021 Feb 01

Fogli Iseppe, A;Morotti, S;Tekook, M;Hoffmann, D;Edwards, A;Dobrev, D;Grandi, E;
| DOI: 10.1016/j.bpj.2020.11.561

Atrial fibrosis is a prominent feature of atrial fibrillation (AF), the most prevalent chronic arrhythmia, and contributes importantly to the vulnerable substrate that promotes and maintains the arrhythmia. While the importance of atrial fibrosis in AF is well-established, and underscored by its potential use as a marker to guide AF ablation therapy, the mechanisms of its formation are largely unknown. Calcium-dependent processes have been involved in AF-promoting structural remodeling, making calcium-handling abnormalities a potentially critical element in AF pathophysiology. However, the exact molecular pathways controlling atrial fibroblast (Fb) proliferation/differentiation and those regulating transcription of extracellular matrix proteins remain largely unknown in any tissue, species, or disease state. To address this unmet need, we have developed a multi-scale modeling framework to 1) quantitively define the major players regulating intracellular calcium homeostasis in human atrial Fbs in both normal sinus rhythm and AF conditions, and to 2) link mechanistically the changes in human atrial Fb calcium signals to downstream outcomes (Fb activation and proliferation and collagen expression) under various profibrotic stimuli. Specifically, this involved building of a new mathematical model of cardiac fibroblast electrophysiology and calcium handling, based on a novel extensive experimental dataset in human atrial Fbs, and coupling it with an experimentally-constrained logic-based network model reflecting the role of calcium in acute (phosphoregulatory) and delayed (transcriptional) human atrial Fb signaling. We demonstrate the use of our computational framework in predicting the effects of angiotensin-II (AngII), a well-known promoter of cardiac fibrosis, on acute human atrial Fb calcium signals and longer-term downstream fibrotic outcomes. We further utilize the model to identify key mechanisms involved in both acute and chronic calcium signaling dysregulation, which could hold therapeutic promise.

Inhibition of Hedgehog signaling alters fibroblast composition in pancreatic cancer

Clinical cancer research : an official journal of the American Association for Cancer Research

2021 Jan 25

Steele, NG;Biffi, G;Kemp, SB;Zhang, Y;Drouillard, D;Syu, LJ;Hao, Y;Oni, TE;Brosnan, E;Elyada, E;Doshi, A;Hansma, C;Espinoza, C;Abbas, A;The, S;Irizarry-Negron, VM;Halbrook, CJ;Franks, N;Hoffman, M;Brown, KL;Carpenter, ES;Nwosu, ZC;Johnson, C;Lima, F;Anderson, MA;Park, Y;Crawford, HC;Lyssiotis, CA;Frankel, TL;Rao, A;Bednar, F;Dlugosz, AA;Preall, J;Tuveson, DA;Allen, B;Pasca di Magliano, M;
PMID: 33495315 | DOI: 10.1158/1078-0432.CCR-20-3715

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog (HH) pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of HH signaling in PDAC have been contradictory, with HH signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how HH pathway inhibition reprograms the PDAC microenvironment. We used a combination of pharmacologic inhibition, gain- and loss- of-function genetic experiments, CyTOF, and single cell RNA-sequencing to study the roles of HH signaling in PDAC. We find that HH signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAFs) compared to inflammatory CAFs (iCAFs). SHH overexpression promotes tumor growth, while HH pathway inhibition with the Smoothened antagonist LDE225 impairs tumor growth. Further, HH pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immune suppression. HH pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.

The Impact of Avpr1a Expression and Host-Microbiome Interactions on Visceral Hypersensitivity

The Journal of Pain

2022 May 01

Kader, L;Willits, A;Baumbauer, K;Young, E;
| DOI: 10.1016/j.jpain.2022.03.026

Visceral hypersensitivity (VH) is commonly cited as a major driver of chronic abdominal pain in “functional” gastrointestinal disorders (e.g., irritable bowel syndrome) where persistent and/or recurrent abdominal pain is the primary unifying symptom regardless of any alterations in bowel habits. The complexity of VH is in part influenced by genetic factors and individual differences in gut microbiome composition, yet specific mechanisms that generate VH remain incompletely understood. Correspondingly, current treatments to primarily focus on symptom management rather than targeting physiological mechanisms responsible for generating VH. We have begun to examine the role of genetic susceptibility and microbiome response dynamics in VH development using a preclinical model of intracolonic zymosan (ZYM) administration in which there are strain differences to VH susceptibility. Preliminary data reveals differential susceptibility between ZYM-induced VH in two closely related C57BL/6 sub strains, one from Taconic Biosciences (C57BL/6NTac) and the other from Jackson Laboratory (C57BL/6J). We have identified a VH candidate gene that encodes the arginine-vasopressin receptor 1A (AVPR1A) protein. We have further observed dynamic strain differences in the location and composition of the gut microbiome in response to ZYM corresponding to VH susceptibility. Ongoing studies are focused on teasing apart the potential bidirectional relationship(s) between genetic susceptibility and host-microbiome interactions in the etiology of VH. Identifying underlying mechanisms that drive VH would provide novel targets for pharmacological intervention and decrease reliance on opioids, which are prescribed at a significantly higher rate to patients who report abdominal pain with no accompanying structural disease. Grant support from R21 NS104789/NS/NINDS (KMB), R03 NS096454/NS/NINDS (KMB), Rita Allen Foundation Award in Pain (KMB), P20GM103418 (EEY and KMB), and a K-INBRE recruitment startup package.

HCV Infection Alters Salivary Gland Histology and Saliva Composition

Journal of dental research

2022 Jan 20

Maldonado, JO;Beach, ME;Wang, Y;Perez, P;Yin, H;Pelayo, E;Fowler, S;Alevizos, I;Grisius, M;Baer, AN;Walitt, B;De Giorgi, V;Alter, HJ;Warner, BM;Chiorini, JA;
PMID: 35045743 | DOI: 10.1177/00220345211049395

Hepatitis C virus (HCV) infection is the most common blood-borne chronic infection in the United States. Chronic lymphocytic sialadenitis and sicca syndrome have been reported in chronic HCV infection. Up to 55% of these patients may have xerostomia; the mechanisms of the xerostomia and salivary gland (SG) hypofunction remain controversial. The objectives of this project are to establish if xerostomia associates with SG and HCV infection and to characterize the structural changes in SG and saliva composition. Eighteen HCV-infected patients with xerostomia were evaluated for SG dysfunction; 6 of these patients (patients 1-6) were further evaluated for SG histopathological changes and changes in saliva composition. The techniques used include clinical and laboratory assessment, SG ultrasonography, histological evaluation, sialochemical and proteomics analysis, and RNA in situ hybridization. All the HCV patients had low saliva flow, chronic sialadenitis, and SG fibrosis and lacked Sjögren syndrome (SS) characteristic autoantibodies. Further evaluation of a subgroup of 6 HCV patients (patients 1-6) demonstrated diffuse lymphocytic infiltrates that are predominantly CD8+ T cells with a significant increase in the number of inflammatory cells. Alcian Blue/periodic acid-Schiff staining showed significant changes in the ratio and intensity of the acinar secretory units of the HCV patients' minor SG. The submandibular glands showed significant ultrasonographic abnormalities in the parenchyma relative to the parotid glands. Significant changes were also observed in the concentration of sodium and mucin 5b. Although no significant correlation was observed between the lymphocytic infiltrates and the years of HCV chronic infection, a positive correlation was observed between HCV RNA-positive epithelial cells and the years of HCV infection. Consistent with the low saliva flow and xerostomia, patients showed changes in several markers of SG acinar and ductal function. Changes in the composition of the saliva suggest that HCV infection can cause xerostomia by mechanisms distinct from SS.

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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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