Activation of PPG neurons following acute stressors differentially involves hindbrain serotonin in male rats

Neuropharmacology

2021 Feb 10

Leon, RM;Borner, T;Stein, LM;Urrutia, NA;De Jonghe, BC;Schmidt, HD;Hayes, MR;
PMID: 33581143 | DOI: 10.1016/j.neuropharm.2021.108477

Within the hindbrain, serotonin (5-HT) functions as a modulator of the central glucagon-like peptide-1 (GLP-1) system. This interaction between 5-HT and GLP-1 is achieved via 5-HT2C and 5-HT3 receptors and is relevant for GLP-1-mediated feeding behavior. The central GLP-1 system is activated by various stressors, activates the hypothalamic pituitary adrenocortical (HPA) axis, and contributes to stress-related behaviors. Whether 5-HT modulates GLP-1's role in the stress response in unknown. We hypothesized that the serotonergic modulation of GLP-1-producing neurons (i.e., PPG neurons) is stimuli-specific and that stressed-induced PPG activity is one of the modalities in which 5-HT plays a role. In this study, we investigated the roles of 5-HT2C and 5-HT3 receptors in mediating the activation of PPG neurons in the nucleus tractus solitarius (NTS) following exposure to three different acute stressors: lithium chloride (LiCl), noncontingent cocaine (Coc), and novel restraint stress (RES). Results showed that increased c-Fos expression in PPG neurons following LiCl and RES-but not Coc-is dependent on hindbrain 5-HT2C and 5-HT3 receptor signaling. Additionally, stressors that depend on 5-HT signaling to activate PPG neurons (i.e., LiCl and RES) increased c-Fos expression in 5-HT-expressing neurons within the caudal raphe (CR), specifically in the raphe magnus (RMg). Finally, we showed that RMg neurons innervate NTS PPG neurons and that some of these PPG neurons lie in close proximity to 5-HT axons, suggesting RMg 5-HT-expressing neurons are the source of 5-HT input responsible for engaging NTS PPG neurons. Together, these findings identify a direct RMg to NTS pathway responsible for the modulatory effect of 5-HT on the central GLP-1 system-specifically via activation of 5-HT2C and 5-HT3 receptors-in the facilitation of acute stress responses.

Implantation of regenerative complexes in traumatic brain injury canine models enhances the reconstruction of neural networks and motor function recovery

Theranostics

2021 Jan 01

Jiang, J;Dai, C;Liu, X;Dai, L;Li, R;Ma, K;Xu, H;Zhao, F;Zhang, Z;He, T;Niu, X;Chen, X;Zhang, S;
PMID: 33391504 | DOI: 10.7150/thno.50540

Rationale: The combination of medical and tissue engineering in neural regeneration studies is a promising field. Collagen, silk fibroin and seed cells are suitable options and have been widely used in the repair of spinal cord injury. In this study, we aimed to determine whether the implantation of a complex fabricated with collagen/silk fibroin (SF) and the human umbilical cord mesenchymal stem cells (hUCMSCs) can promote cerebral cortex repair and motor functional recovery in a canine model of traumatic brain injury (TBI). Methods: A porous scaffold was fabricated with cross-linked collagen and SF. Its physical properties and degeneration rate were measured. The scaffolds were co-cultured with hUCMSCs after which an implantable complex was formed. After complex implantation to a canine model of TBI, the motor evoked potential (MEP) and magnetic resonance imaging (MRI) were used to evaluate the integrity of the cerebral cortex. The neurologic score, motion capture, surface electromyography (sEMG), and vertical ground reaction force (vGRF) were measured in the analysis of motor functions. In vitro analysis of inflammation levels was performed by Elisa while immunohistochemistry was used in track the fate of hUCMSCs. In situ hybridization, transmission electron microscope, and immunofluorescence were used to assess neural and vascular regeneration. Results: Favorable physical properties, suitable degradation rate, and biocompatibility were observed in the collagen/SF scaffolds. The group with complex implantation exhibited the best cerebral cortex integrity and motor functions. The implantation also led to the regeneration of more blood vessels and nerve fibers, less glial fibers, and inflammatory factors. Conclusion: Implantation of this complex enhanced therapy in traumatic brain injury (TBI) through structural repair and functional recovery. These effects exhibit the translational prospects for the clinical application of this complex.

Correlation of tgfb2 mRNA expression to disease progression in a time course of chronic biliary liver disease

37. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber

2021 Jan 01

Albin, J;Meindl-Beinker, N;Ebert, M;Teufel, A;Dooley, S;Dropmann, A;
| DOI: 10.1055/s-0040-1721973

Question To identify the cellular source of TgfB2 in a time course of cholestatic liver disease using Abcb4-KO mice and PSC patients, and to correlate findings to disease stages. Methods Liver samples from PSC liver biopsies and Abcb4-KO mice at the age of 2-, 6-, 8- and 12-months were stained for HE, Sirius Red and Orcein to visualize inflammation and fibrosis. Morphological evaluation was performed using Ishak and Nakanuma scoring systems. Tgfb2 mRNA expression was analysed by in situ hybridisation using the RNAscope technique and then compared to age matched wildtype Balb/c mice and disease-free human liver as well as PSC samples. Results In Abcb4-KO tissues, we found an increase in grade and stage of fibrosis and inflammation with advancing disease progression using both scoring systems in comparison to wild type mice. Disease progression was faster in female than in male mice, especially with regard to inflammation. Subscores, e.g. portal tract inflammation and interface hepatitis increased first, while confluent necrosis occurred not before the age of 12 months. Tgfb2 mRNA was expressed in areas of proliferating bile ducts and fibrotically rearranged tissue at all stages of cholestatic disease. Both murine and human livers showing higher Ishak and Nakanuma scores also showed stronger tgfb2 expression, particularly in samples with a high grade of portal inflammation. We are currently performing costaining with cell type/cell fate markers to specifically identify the cell type that upregulates TGFb2 expression. Conclusions The expression of tgfb2 mRNA increased with disease progression of Abcb4-KO mice, whereby prominent inflammatory grades present with the highest expression levels in mice and human.

Mouse Brain Regions Activated By Isoflurane Anesthesia Marked By C-Fos Labeling

The Journal of Pain

2023 Apr 01

Yuan, M;Zhao, J;McGinnis, A;Mathew, J;Wang, F;Ji, R;
| DOI: 10.1016/j.jpain.2023.02.115

Although anesthesia is commonly used in the fields of medicine and scientific research, the neural mechanisms and circuits through which it produces analgesia is still unclear. Utilizing c-fos labeling of neuronal activity, this project aimed to investigate the brain regions of C57BL/6 mice, which become activated subsequent to isoflurane anesthesia. RNAscope in situ hybridization was used to examine c-fos mRNA activation in the brain. Confocal microscopy was utilized to locate and characterize brain regions displaying c-Fos activation. Finally, manual quantification of c-fos activation in identified brain regions was conducted through Fiji software. The brain regions identified resemble brain areas that have been associated with pain regulation in literature, including the central nucleus of amygdala (CeA), paraventricular nucleus of the hypothalamus (PVN), centrally-projecting Edinger-Westphal nucleus (EWcp), piriform cortex (PC), and para-supraoptic nucleus (ParaSON). Furthermore, the CeA displayed the greatest average number of positive cells and the densest activation, supporting its importance in pain and analgesia. The identified brain regions validate the prominent findings of prior studies, which also found c-Fos activation subsequent to isoflurane anesthesia in the CeA, PVN, and ParaSON (Hua et al., Nat Neurosci, 2020). New regions of c-fos activation, including the EWcp and PC, found in this study are in need of further exploration. PC activation may also be caused by smell from isoflurane. The connections and coordination which the identified brain regions have in producing analgesia is also an area for future investigation. This study is supported by Duke University Anesthesiology Fund and NIH grant R01-DE29342. This study is supported by Duke University Anesthesiology Fund and NIH grant R01-DE29342.

Effect of diabetic foot ulcers and other risk factors on the prevalence of lower extremity amputation: A meta-analysis

International wound journal

2023 Apr 24

Zhang, H;Huang, C;Bai, J;Wang, J;
PMID: 37095728 | DOI: 10.1111/iwj.14179

A meta-analysis study was conducted to measure the consequence of diabetic foot ulcers (DFUs) and other risk factors (RFs) on the prevalence of lower extremity amputation (LEA). A comprehensive literature inspection till February 2023 was applied and 2765 interrelated studies were reviewed. Of the 32 chosen studies enclosed, 9934 subjects were in the chosen studies' starting point, and 2906 of them were with LEA. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the effect of DFUs and other RFs on the prevalence of LEA by the continuous and dichotomous approaches and a fixed or random effect model. Male gender (OR, 1.30; 95% CI, 1.17-1.44, P < .001), smoking (OR, 1.24; 95% CI, 1.01-1.53, P = .04), previous foot ulcer (OR, 2.69; 95% CI, 1.93-3.74, P < .001), osteomyelitis (OR, 3.87; 95% CI, 2.28-6.57, P < .001), gangrene (OR, 14.45; 95% CI, 7.03-29.72, P < .001), hypertension (OR, 1.17; 95% CI, 1.03-1.33, P = .01), and white blood cells count (WBCC) (MD, 2.05; 95% CI, 1.37-2.74, P < .001) were significantly shown to be an RF in LEA in subjects with DFUs. Age (MD, 0.81; 95% CI, -0.75 to 2.37, P = .31), body mass index (MD, -0.55; 95% CI, -1.15 to 0.05, P = .07), diabetes mellitus type (OR, 0.99; 95% CI, 0.63-1.56, P = .96), and glycated haemoglobin (MD, 0.33; 95% CI, -0.15 to 0.81, P = .17) were not shown to be an RF in LEA in subjects with DFUs. Male gender, smoking, previous foot ulcer, osteomyelitis, gangrene, hypertension, and WBCC were significantly shown to be an RF in LEA in subjects with DFUs. However, age and diabetes mellitus type were not shown to be RF in LEA in subjects with DFUs. However, caused of the small sample sizes of several chosen studies for this meta-analysis, care must be exercised when dealing with its values.

FOXF1 Regulates Alveolar Epithelial Morphogenesis Through Transcriptional Activation of Mesenchymal WNT5A

American journal of respiratory cell and molecular biology

2022 Dec 21

Reza, AA;Kohram, F;Reza, HA;Kalin, TR;Kannan, PS;Zacharias, WJ;Kalinichenko, VV;
PMID: 36542853 | DOI: 10.1165/rcmb.2022-0191OC

Mutations in the FOXF1 gene, encoding the mesenchymal Forkhead Box (FOX) transcription factor, are linked to Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV), a severe congenital disorder associated with the loss of alveolar capillaries and lung hypoplasia. While proangiogenic functions of FOXF1 have been extensively studied, the role of FOXF1 in mesenchymal-epithelial signaling during lung development remains uncharacterized. Herein, we utilized murine lung organoids to demonstrate that the S52F FOXF1 mutation (found in ACDMPV patients) stimulates canonical WNT/β-catenin signaling in type 2 alveolar epithelial cells (AEC2s), leading to increased proliferation of AEC2s and decreased differentiation of AEC2s into AEC1s. Alveolar organoids containing Foxf1WT/S52F lung fibroblasts and wild-type epithelial cells grew faster on Matrigel and exhibited AEC2 hyperplasia. AEC2 hyperplasia and loss of AEC1s were found in the lungs of Foxf1WT/S52F embryos, a mouse model of ACDMPV. Activation of canonical WNT/β-catenin signaling in AEC2s of lung organoids and Foxf1WT/S52F mice was associated with decreased expression of non-canonical WNT5A ligand in lung fibroblasts. Mechanistically, FOXF1 directly activates the Wnt5a gene transcription through an evolutionarily conserved +6320/+6326 region located in the first intron of the Wnt5a gene. Site-directed mutagenesis of the +6320/+6326 region prevented the transcriptional activation of the Wnt5a enhancer by FOXF1. Treatment with exogenous WNT5A ligand inhibited the effects of the S52F FOXF1 mutation on canonical WNT/β-catenin signaling in alveolar organoids, preventing aberrant AEC2 cell expansion and restoring differentiation of AEC1s. Activation of either FOXF1 or WNT5A may provide an attractive strategy to improve lung function in ACDMPV patients.

FP.29 AAV-CRISPR-Cas13 gene therapy for FSHD: DUX4 gene silencing efficacy and immune responses to Cas13b protein

Neuromuscular Disorders

2022 Oct 01

Rashnonejad, A;Amini-Chermahini, G;Taylor, N;Fowler, A;Kraus, E;King, O;Harper, S;
| DOI: 10.1016/j.nmd.2022.07.255

Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies, ranging from 1 in 8,333 to 1 in 20,000. Currently no treatment exists that alters the course of FSHD, and therapy development remains an unmet need in the field. Abnormal reactivation of the DUX4 gene in skeletal muscle has emerged as an underlying cause of muscle weakness and wasting in FSHD. We propose that DUX4 silencing is the most direct route to FSHD therapy. Toward this goal, we developed an AAV6-CRISPR-Cas13 strategy to silence DUX4 mRNA. Cas13 targets and cleaves RNA instead of DNA, and avoids potential risks of permanent off-target genome editing that could arise with DNA-targeting systems. Intramuscular delivery of an AAV6 vector encoding a PspCas13b enzyme and DUX4-targeting guide RNAs reduced DUX4 mRNA by >50% and improved histopathological outcomes in FSHD mice. To investigate possible off-target effects, we performed RNA-seq of treated versus control or untreated human myoblasts and also examined potential collateral RNA cleavage activity using a dual reporter system. Although we did not detect collateral cleavage, our RNA-sequencing results suggested some guide RNAs could induce potential off-target gene expression changes. We are currently exploring mechanisms to explain these differential off-target effects. To address whether PspCas13b can activate a mammalian host immune response, we injected wild-type mice with AAV-Cas13b and investigated immune cell infiltration and pro-inflammatory cytokine profiles. We find evidence of an immune response against PspCas13b in injected mouse muscles. Importantly, transient immunosuppression reduced immune responses to Cas13b in treated animals. In conclusion, our data support that Cas13b can target and reduce DUX4 expression in FSHD muscles, but minimizing cellular immune response may be necessary to translate AAV-Cas13b therapy.

Molecular and Circuit-Specific Analysis of Locus Coeruleus-Prefrontal Networks During a Touchscreen Rodent Continuous Performance Test

Biological Psychiatry

2021 May 01

Hallock, H;Valerino, J;DeBrosse, A;Noback, M;Quillian, H;Barrow, J;Jaffe, A;Carr, G;Martinowich, K;
| DOI: 10.1016/j.biopsych.2021.02.299

Background Aberrant prefrontal cortex (PFC) activity occurs in patients with neuropsychiatric disorders during sustained attention tasks, suggesting that PFC dysfunction underlies attention deficits in these patients. However, the mechanisms by which the PFC regulates sustained attention remain unclear. Methods Behavioral testing and c-Fos immunohistochemistry during performance of a touchscreen sustained attention task (rCPT) in mice. In vivo calcium and norepinephrine imaging to assess patterns of activity during the rCPT. In vivo electrophysiology to detect how the medial PFC (mPFC) and locus coeruleus (LC) communicate during the rCPT. For assessment of molecular function in subsets of mPFC neurons that receive contact from the LC, we used RNAscope and bulk RNA-sequencing. Results We found that the LC and mPFC synchronized their activity during the rCPT, and imaging of neuronal activity in the mPFC revealed that mPFC neurons have heterogeneous response patterns during rCPT performance, with some neurons increasing their calcium activity during stimulus orientation and some neurons increasing their calcium activity during behavioral responses. To determine the molecular identities of mPFC neurons that connect with the LC, we used RNAscope to find that mPFC neurons receiving LC contact are primarily GABAergic, while mPFC neurons projecting to the LC are primarily excitatory. Using bulk RNA-sequencing, we further found that depolarization of LC inputs to the mPFC caused enrichment of a host of transcripts in mPFC tissue. Conclusions We uncover unique biomarkers of neuronal function in the LC-mPFC circuit, providing insight into potential therapeutic targets for attentional regulation in disorders such as ADHD, major depressive disorder, and schizophrenia.

Covid-19 Interstitial Pneumonia: Histological and Immunohistochemical Features on Cryobiopsies

Respiration; international review of thoracic diseases

2021 Mar 16

Doglioni, C;Ravaglia, C;Chilosi, M;Rossi, G;Dubini, A;Pedica, F;Piciucchi, S;Vizzuso, A;Stella, F;Maitan, S;Agnoletti, V;Puglisi, S;Poletti, G;Sambri, V;Pizzolo, G;Bronte, V;Wells, AU;Poletti, V;
PMID: 33725700 | DOI: 10.1159/000514822

The pathogenetic steps leading to Covid-19 interstitial pneumonia remain to be clarified. Most postmortem studies to date reveal diffuse alveolar damage as the most relevant histologic pattern. Antemortem lung biopsy may however provide more precise data regarding the earlier stages of the disease, providing a basis for novel treatment approaches. To ascertain the morphological and immunohistochemical features of lung samples obtained in patients with moderate Covid-19 pneumonia. Transbronchial lung cryobiopsy was carried out in 12 Covid-19 patients within 20 days of symptom onset. Histopathologic changes included spots of patchy acute lung injury with alveolar type II cell hyperplasia, with no evidence of hyaline membranes. Strong nuclear expression of phosphorylated STAT3 was observed in >50% of AECII. Interalveolar capillaries showed enlarged lumen and were in part arranged in superposed rows. Pulmonary venules were characterized by luminal enlargement, thickened walls, and perivascular CD4+ T-cell infiltration. A strong nuclear expression of phosphorylated STAT3, associated with PD-L1 and IDO expression, was observed in endothelial cells of venules and interstitial capillaries. Alveolar spaces macrophages exhibited a peculiar phenotype (CD68, CD11c, CD14, CD205, CD206, CD123/IL3AR, and PD-L1). Morphologically distinct features were identified in early stages of Covid-19 pneumonia, with epithelial and endothelial cell abnormalities different from either classical interstitial lung diseases or diffuse alveolar damage. Alveolar type II cell hyperplasia was a prominent event in the majority of cases. Inflammatory cells expressed peculiar phenotypes. No evidence of hyaline membranes and endothelial changes characterized by IDO expression might in part explain the compliance and the characteristic pulmonary vasoplegia observed in less-advanced Covid-19 pneumonia.

Myocardial TGFβ2 Is Required for Atrioventricular Cushion Remodeling and Myocardial Development

Journal of Cardiovascular Development and Disease

2021 Mar 02

Bhattacharya, A;Al-Sammarraie, N;Gebere, M;Johnson, J;Eberth, J;Azhar, M;
| DOI: 10.3390/jcdd8030026

Among the three transforming growth factor beta (TGFβ) ligands, TGFβ2 is essential for heart development and is produced by multiple cell types, including myocardium. Heterozygous mutations in TGFB2 in patients of connective tissue disorders result in congenital heart defects and adult valve malformations, including mitral valve prolapse (MVP) with or without regurgitation. Tgfb2 germline knockout fetuses exhibit multiple cardiac defects but the role of myocardial-TGFβ2 in heart development is yet to be elucidated. Here, myocardial Tgfb2 conditional knockout (CKO) embryos were generated by crossing Tgfb2flox mice with Tgfb2+/−; cTntCre mice. Tgfb2flox/− embryos were normal, viable. Cell fate mapping was done using dual-fluorescent mT/mG+/− mice. Cre-mediated Tgfb2 deletion was assessed by genomic PCR. RNAscope in situ hybridization was used to detect the loss of myocardial Tgfb2 expression. Histological, morphometric, immunohistochemical, and in situ hybridization analyses of CKOs and littermate controls at different stages of heart development (E12.5–E18.5) were used to determine the role of myocardium-derived TGFβ2 in atrioventricular (AV) cushion remodeling and myocardial development. CKOs exhibit a thin ventricular myocardium, AV cushion remodeling defects and developed incomplete AV septation defects. The loss of myocardial Tgfb2 resulted in impaired cushion maturation and dysregulated cell death. Phosphorylated SMAD2, a surrogate for TGFβ signaling, was “paradoxically” increased in both AV cushion mesenchyme and ventricular myocardium in the CKOs. Our results indicate that TGFβ2 produced by cardiomyocytes acting as cells autonomously on myocardium and via paracrine signaling on AV cushions are required for heart development.

Mechanisms and regulation of IL-22-mediated intestinal epithelial homeostasis and repair

Life sciences

2021 Feb 10

Patnaude, L;Mayo, M;Mario, R;Wu, X;Knight, H;Creamer, K;Wilson, S;Pivorunas, V;Karman, J;Phillips, L;Dunstan, R;Kamath, RV;McRae, B;Terrillon, S;
PMID: 33581125 | DOI: 10.1016/j.lfs.2021.119195

Ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease (IBD), are chronic inflammatory disorders of the intestine for which key elements in disease initiation and perpetuation are defects in epithelial barrier integrity. Achieving mucosal healing is essential to ameliorate disease outcome and so new therapies leading to epithelial homeostasis and repair are under investigation. This study was designed to determine the mechanisms by which IL-22 regulates intestinal epithelial cell function. Human intestinal organoids and resections, as well as mice were used to evaluate the effect of IL-22 on stem cell expansion, proliferation and expression of mucus components. IL-22 effect on barrier function was assessed in polarized T-84 cell monolayers. Butyrate co-treatments and organoid co-cultures with immune cells were performed to monitor the impact of microbial-derived metabolites and inflammatory environments on IL-22 responses. IL-22 led to epithelial stem cell expansion, proliferation, barrier dysfunction and anti-microbial peptide production in human and mouse models evaluated. IL-22 also altered the mucus layer by inducing an increase in membrane mucus but a decrease in secreted mucus and goblet cell content. IL-22 had the same effect on anti-microbial peptides and membrane mucus in both healthy and IBD human samples. In contrast, this IL-22-associated epithelial phenotype was different when treatments were performed in presence of butyrate and organoids co-cultured with immune cells. Our data indicate that IL-22 promotes epithelial regeneration, innate defense and membrane mucus production, strongly supporting the potential clinical utility of IL-22 as a mucosal healing therapy in IBD.

Rad-GTPase contributes to heart rate via L-type calcium channel regulation

Journal of molecular and cellular cardiology

2021 Feb 06

Levitan, BM;Ahern, BM;Aloysius, A;Brown, L;Wen, Y;Andres, DA;Satin, J;
PMID: 33556393 | DOI: 10.1016/j.yjmcc.2021.01.005

Sinoatrial node cardiomyocytes (SANcm) possess automatic, rhythmic electrical activity. SAN rate is influenced by autonomic nervous system input, including sympathetic nerve increases of heart rate (HR) via activation of β-adrenergic receptor signaling cascade (β-AR). L-type calcium channel (LTCC) activity contributes to membrane depolarization and is a central target of β-AR signaling. Recent studies revealed that the small G-protein Rad plays a central role in β-adrenergic receptor directed modulation of LTCC. These studies have identified a conserved mechanism in which β-AR stimulation results in PKA-dependent Rad phosphorylation: depletion of Rad from the LTCC complex, which is proposed to relieve the constitutive inhibition of CaV1.2 imposed by Rad association. Here, using a transgenic mouse model permitting conditional cardiomyocyte selective Rad ablation, we examine the contribution of Rad to the control of SANcm LTCC current (ICa,L) and sinus rhythm. Single cell analysis from a recent published database indicates that Rad is expressed in SANcm, and we show that SANcm ICa,L was significantly increased in dispersed SANcm following Rad silencing compared to those from CTRL hearts. Moreover, cRadKO SANcm ICa,L was not further increased with β-AR agonists. We also evaluated heart rhythm in vivo using radiotelemetered ECG recordings in ambulating mice. In vivo, intrinsic HR is significantly elevated in cRadKO. During the sleep phase cRadKO also show elevated HR, and during the active phase there is no significant difference. Rad-deletion had no significant effect on heart rate variability. These results are consistent with Rad governing LTCC function under relatively low sympathetic drive conditions to contribute to slower HR during the diurnal sleep phase HR. In the absence of Rad, the tonic modulated SANcm ICa,L promotes elevated sinus HR. Future novel therapeutics for bradycardia targeting Rad - LTCC can thus elevate HR while retaining βAR responsiveness.

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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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