Refine Probe List

Follistatin mediates learning and synaptic plasticity via regulation of Asic4 expression in the hippocampus

Proceedings of the National Academy of Sciences of the United States of America

2021 Sep 28

Chen, YJ;Deng, SM;Chen, HW;Tsao, CH;Chen, WT;Cheng, SJ;Huang, HS;Tan, BC;Matzuk, MM;Flint, J;Huang, GJ;
PMID: 34544873 | DOI: 10.1073/pnas.2109040118

The biological mechanisms underpinning learning are unclear. Mounting evidence has suggested that adult hippocampal neurogenesis is involved although a causal relationship has not been well defined. Here, using high-resolution genetic mapping of adult neurogenesis, combined with sequencing information, we identify follistatin (Fst) and demonstrate its involvement in learning and adult neurogenesis. We confirmed that brain-specific Fst knockout (KO) mice exhibited decreased hippocampal neurogenesis and demonstrated that FST is critical for learning. Fst KO mice exhibit deficits in spatial learning, working memory, and long-term potentiation (LTP). In contrast, hippocampal overexpression of Fst in KO mice reversed these impairments. By utilizing RNA sequencing and chromatin immunoprecipitation, we identified Asic4 as a target gene regulated by FST and show that Asic4 plays a critical role in learning deficits caused by Fst deletion. Long-term overexpression of hippocampal Fst in C57BL/6 wild-type mice alleviates age-related decline in cognition, neurogenesis, and LTP. Collectively, our study reveals the functions for FST in adult neurogenesis and learning behaviors.

Norrie disease protein is essential for cochlear hair cell maturation

Proceedings of the National Academy of Sciences of the United States of America

2021 Sep 28

Hayashi, Y;Chiang, H;Tian, C;Indzhykulian, AA;Edge, ASB;
PMID: 34544869 | DOI: 10.1073/pnas.2106369118

Mutations in the gene for Norrie disease protein (Ndp) cause syndromic deafness and blindness. We show here that cochlear function in an Ndp knockout mouse deteriorated with age: At P3-P4, hair cells (HCs) showed progressive loss of Pou4f3 and Gfi1, key transcription factors for HC maturation, and Myo7a, a specialized myosin required for normal function of HC stereocilia. Loss of expression of these genes correlated to increasing HC loss and profound hearing loss by 2 mo. We show that overexpression of the Ndp gene in neonatal supporting cells or, remarkably, up-regulation of canonical Wnt signaling in HCs rescued HCs and cochlear function. We conclude that Ndp secreted from supporting cells orchestrates a transcriptional network for the maintenance and survival of HCs and that increasing the level of β-catenin, the intracellular effector of Wnt signaling, is sufficient to replace the functional requirement for Ndp in the cochlea.

A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma

Cell reports

2021 Sep 28

Milon, B;Shulman, ED;So, KS;Cederroth, CR;Lipford, EL;Sperber, M;Sellon, JB;Sarlus, H;Pregernig, G;Shuster, B;Song, Y;Mitra, S;Orvis, J;Margulies, Z;Ogawa, Y;Shults, C;Depireux, DA;Palermo, AT;Canlon, B;Burns, J;Elkon, R;Hertzano, R;
PMID: 34592158 | DOI: 10.1016/j.celrep.2021.109758

Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells of the inner ear, dysfunction of its lateral wall, axonal retraction of type 1C spiral ganglion neurons, and activation of the immune response. We use RiboTag and single-cell RNA sequencing to survey the cell-type-specific molecular landscape of the mouse inner ear before and after noise trauma. We identify induction of the transcription factors STAT3 and IRF7 and immune-related genes across all cell-types. Yet, cell-type-specific transcriptomic changes dominate the response. The ATF3/ATF4 stress-response pathway is robustly induced in the type 1A noise-resilient neurons, potassium transport genes are downregulated in the lateral wall, mRNA metabolism genes are downregulated in outer hair cells, and deafness-associated genes are downregulated in most cell types. This transcriptomic resource is available via the Gene Expression Analysis Resource (gEAR; https://umgear.org/NIHL) and provides a blueprint for the rational development of drugs to prevent and treat NIHL.

Factors modulating the incubation of drug and non-drug craving and their clinical implications

Neuroscience and biobehavioral reviews

2021 Sep 28

Venniro, M;Reverte, I;Ramsey, LA;Papastrat, KM;D'Ottavio, G;Milella, MS;Li, X;Grimm, JW;Caprioli, D;
PMID: 34597716 | DOI: 10.1016/j.neubiorev.2021.09.050

It was suggested in 1986 that cue-induced cocaine craving increases progressively during early abstinence and remains high during extended periods of times. Clinical evidence now supports this hypothesis and that this increase is not specific to cocaine but rather generalize across several drugs of abuse. Investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after abstinence from intravenous drug or palatable food self-administration. Incubation of craving is susceptible to variation in magnitude as a function of biological and/or the environmental circumstances surrounding the individual. During the last decade, the neurobiological correlates of the modulatory role of biological (sex, age, genetic factors) and environmental factors (environmental enrichment and physical exercise, sleep architecture, acute and chronic stress, abstinence reinforcement procedures) on incubation of drug craving has been investigated. In this review we summarized the behavioral procedures adopted, the key underlying neurobiological correlates and clinical implications of these studies.

HISTOLOGICAL FINDINGS IN TRANSBRONCHIAL CRYOBIOPSIES OBTAINED FROM PATIENTS AFTER COVID-19

Chest

2021 Sep 25

Culebras, M;Loor, K;Sansano, I;Persiva, Ó;Clofent, D;Polverino, E;Felipe, A;Osorio, J;Muñoz, X;Álvarez, A;Se-COVID-19 team, ;
PMID: 34582842 | DOI: 10.1016/j.chest.2021.09.016

YAP regulates alveolar epithelial cell differentiation and AGER via NFIB/KLF5/NKX2-1

iScience

2021 Sep 24

Gokey, JJ;Snowball, J;Sridharan, A;Sudha, P;Kitzmiller, JA;Xu, Y;Whitsett, JA;
PMID: 34466790 | DOI: 10.1016/j.isci.2021.102967

Ventilation is dependent upon pulmonary alveoli lined by two major epithelial cell types, alveolar type-1 (AT1) and 2 (AT2) cells. AT1 cells mediate gas exchange while AT2 cells synthesize and secrete pulmonary surfactants and serve as progenitor cells which repair the alveoli. We developed transgenic mice in which YAP was activated or deleted to determine its roles in alveolar epithelial cell differentiation. Postnatal YAP activation increased epithelial cell proliferation, increased AT1 cell numbers, and caused indeterminate differentiation of subsets of alveolar cells expressing atypical genes normally restricted to airway epithelial cells. YAP deletion increased expression of genes associated with mature AT2 cells. YAP activation enhanced DNA accessibility in promoters of transcription factors and motif enrichment analysis predicted target genes associated with alveolar cell differentiation. YAP participated with KLF5, NFIB, and NKX2-1 to regulate AGER. YAP plays a central role in a transcriptional network that regulates alveolar epithelial differentiation.

CONSEQUENCES OF mTOR INHIBITION ON AAV HEPATIC TRANSDUCTION EFFICACY

Human gene therapy

2021 Sep 24

Perez-Iturralde, A;Carte, B;Aldabe, R;
PMID: 34555962 | DOI: 10.1089/hum.2021.171

The efficiency of recombinant Adeno-associated virus vectors (AAV) transducing host cells is very low, limiting their therapeutic potential in patients. There are several cellular pathways interacting and interfering with the journey of the AAV from the cell surface to the nucleus, opening the possibility to enhance AAV transduction by modifying these interactions. In this study, we explored the results of AAV hepatic transduction when different mTOR inhibitors.- rapamycin, MLN0128, RapaLink-1 -were used in preconditioned juvenile and adult mice. We confirmed rapamycin as an AAV hepatic transduction enhancer in juvenile and adult mice; however, RapaLink-1, a stronger mTOR inhibitor and a clear hepatic autophagy inducer, had no positive effect. Moreover, MLN0128 reduced AAV hepatic transduction. Therefore, our results show a complex interaction between the mTOR pathway and AAV-mediated hepatic transduction and indicate that mTOR inhibition is not a straightforward strategy for improving AAV transduction. More studies are necessary to elucidate the molecular mechanisms involve in the positive and negative effects of mTOR inhibitors on AAV transduction efficiency.

High CYP27A1 expression is a biomarker of favorable prognosis in premenopausal patients with estrogen receptor positive primary breast cancer

NPJ breast cancer

2021 Sep 23

Inasu, M;Bendahl, PO;Fernö, M;Malmström, P;Borgquist, S;Kimbung, S;
PMID: 34556659 | DOI: 10.1038/s41523-021-00333-6

27-hydroxycholesterol (27HC), synthesized from cholesterol by the enzyme CYP27A1, differentially impacts estrogen receptor positive (ER+) breast cancer (BC) cell growth depending on estrogen levels. This study examined the association between CYP27A1 expression and prognosis in a cohort of 193 premenopausal patients with lymph node-negative primary BC with limited exposure to adjuvant systemic cancer treatments. In multivariable analyses among patients with ER+ tumors, high CYP27A1 protein and mRNA expressions were associated with four- and eight-fold reductions in the incidence of distant recurrence-free survival events: HRadj = 0.26, 95% CI = 0.07-0.93 and HRadj = 0.13, 95% CI = 0.03-0.60, respectively. In vitro studies revealed that 27HC treatment potently inhibited ER+ BC cell proliferation under lipid-depleted conditions regardless of estradiol levels, transcriptionally mediated through the downregulation of ER signaling with a concomitant upregulation of cholesterol export. Importantly, if validated, these results may have implications for adjuvant treatment decisions in premenopausal patients, especially when de-escalation of therapy is being considered.

Interleukin-6 and lactate dehydrogenase expression in a novel ex vivo rocking model of equine corneal epithelial wound healing

Veterinary ophthalmology

2021 Sep 23

Wehrman, RF;Genschel, U;Charli, A;Kanthasamy, AG;Allbaugh, RA;Ben-Shlomo, G;
PMID: 34553825 | DOI: 10.1111/vop.12935

To establish a physiologically relevant ex vivo model of equine corneal epithelial wound healing.Fourteen equine corneas were randomly assigned to one of two groups: wounded (n = 8) or unwounded (n = 6) controls. In the wounded group, the axial corneal epithelium was removed by applying a 6 mm filter paper disk soaked in 1N-NaOH for 60 s. Corneas were subsequently cultured using an air-liquid interface model. Evaluation of corneal healing was performed daily, and culture medium was collected. Corneas were randomly assigned to undergo processing via histopathology and RNAscope in situ hybridization for interleukin-6 (IL-6) and alpha-smooth muscle actin (αSMA) expression at T24, T48, and T72 h after wounding. Media of the cultured corneas were evaluated for the presence of lactate dehydrogenase (LDH) by a colorimetric assay.The ulcerated area of the wounded corneas decreased over time and all corneas healed within 72 h. Histologically, normal corneal architecture was observed including healthy epithelium (in areas other than the ulcerated ones), minimal stromal edema, intact endothelium, and Descemet's membrane. IL-6 expression was increased in wounded corneas compared with unwounded controls. LDH expression was elevated for both wounded and unwounded corneas at T24 but decreased substantially and was not detected at T48 in media from wounded and unwounded corneas, respectively. No αSMA expression was detected from either wounded or unwounded corneas.The equine air-liquid interface, ex vivo, corneal epithelial wound healing model is effective and physiologically relevant. This model can be used in future studies evaluating various corneal therapies.

Detection of rabbit hemorrhagic disease virus 2 in formalin-fixed, paraffin-embedded tissues via in situ hybridization

Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc

2021 Sep 23

O'Toole, AD;Zhang, J;Williams, LBA;Brown, CC;
PMID: 34554024 | DOI: 10.1177/10406387211047561

Formalin-fixed, paraffin-embedded tissues from European rabbits (Oryctolagus cuniculus) that succumbed to rabbit hemorrhagic disease virus 2 (RHDV2; Lagovirus GI.2) during the 2019 outbreak in Washington, USA, were utilized for in situ hybridization via RNAscope (ACDBio). This detection method was both sensitive and specific, with no staining in tissues from RHDV- (Lagovirus GI.1) and RHDV2-negative rabbits, and only slight background staining of RHDV-positive rabbits; RHDV2-positive tissues had bright-red cytoplasmic staining. Although much of the viral mRNA detection was consistent with previously described antigen detection via immunohistochemistry of the liver, lungs, and spleen, there was also significant glomerular staining in the kidneys, and endothelial staining within blood vessels of almost all organs. We validated the RNAscope technique for detection of RHDV2 mRNA in formalin-fixed, paraffin-embedded tissues, with increased sensitivity from previous techniques, and identified additional affected cell types that may contribute to the understanding of pathogenesis.

Transgenic overexpression of the miR-200b/200a/429 cluster inhibits mammary tumor initiation

Translational oncology

2021 Sep 22

Watson, KL;Yi, R;Moorehead, RA;
PMID: 34562686 | DOI: 10.1016/j.tranon.2021.101228

The miR-200 family consists of five members expressed as two clusters: miR-200c/141 cluster and miR-200b/200a/429 cluster. In the mammary gland, miR-200s maintain epithelial identity by decreasing the expression of mesenchymal markers leading to high expression of epithelial markers. While the loss of miR-200s is associated with breast cancer growth and metastasis the impact of miR-200 expression on mammary tumor initiation has not been investigated. Using mammary specific expression of the miR-200b/200a/429 cluster in transgenic mice, we found that elevated expression miR-200s could almost completely prevent mammary tumor development. Only 1 of 16 MTB-IGFIRba429 transgenic mice (expressing both the IGF-IR and miR-200b/200a/429 transgenes) developed a mammary tumor while 100% of MTB-IGFIR transgenic mice (expressing only the IGF-IR transgene) developed mammary tumors. RNA sequencing, qRT-PCR, and immunohistochemistry of mammary tissue from 55-day old mice found Spp1, Saa1, and Saa2 to be elevated in mammary tumors and inhibited by miR-200b/200a/429 overexpression. This study suggests that miR-200s could be used as a preventative strategy to protect women from developing breast cancer. One concern with this approach is the potential negative impact miR-200 overexpression may have on mammary function. However, transgenic overexpression of miR-200s, on their own, did not significantly impact mammary ductal development indicating the miR-200 overexpression should not significantly impact mammary function. Thus, this study provides the initial foundation for using miR-200s for breast cancer prevention and additional studies should be performed to identify strategies for increasing mammary miR-200 expression and determine whether miR-200s can prevent mammary tumor initiation by other genetic alterations.

Single-nucleus transcriptome analysis reveals cell-type-specific molecular signatures across reward circuitry in the human brain

Neuron

2021 Sep 21

Tran, MN;Maynard, KR;Spangler, A;Huuki, LA;Montgomery, KD;Sadashivaiah, V;Tippani, M;Barry, BK;Hancock, DB;Hicks, SC;Kleinman, JE;Hyde, TM;Collado-Torres, L;Jaffe, AE;Martinowich, K;
PMID: 34582785 | DOI: 10.1016/j.neuron.2021.09.001

Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.

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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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