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Biomedicines
2022 Feb 07
Chen, K;Wang, P;Chen, J;Ying, Y;Chen, Y;Gilson, E;Lu, Y;Ye, J;
PMID: 35203601 | DOI: 10.3390/biomedicines10020392
Ataxia-telangiectasia mutated (ATM) is a key DNA damage signaling kinase that is mutated in humans with ataxia-telangiectasia (A-T) syndrome. This syndrome is characterized by neurodegeneration, immune abnormality, cancer predisposition, and premature aging. To better understand the function of ATM in vivo, we engineered a viable zebrafish model with a mutated atm gene. Zebrafish atm loss-of-function mutants show characteristic features of A-T-like motor disturbance, including coordination disorders, immunodeficiency, and tumorigenesis. The immunological disorder of atm homozygote fish is linked to the developmental blockade of hematopoiesis, which occurs at the adulthood stage and results in a decrease in infection defense but, with little effect on wound healing. Malignant neoplasms found in atm mutant fish were mainly nerve sheath tumors and myeloid leukemia, which rarely occur in A-T patients or Atm-/- mice. These results underscore the importance of atm during immune cell development. This zebrafish A-T model opens up a pathway to an improved understanding of the molecular basis of tumorigenesis in A-T and the cellular role of atm.
Neurobiology of disease
2022 Feb 24
Studtmann, C;Ladislav, M;Topolski, MA;Safari, M;Swanger, SA;
PMID: 35219855 | DOI: 10.1016/j.nbd.2022.105672
Thalamocortical network dysfunction contributes to seizures and sleep deficits in Dravet syndrome (DS), an infantile epileptic encephalopathy, but the underlying molecular and cellular mechanisms remain elusive. DS is primarily caused by mutations in the SCN1A gene encoding the voltage-gated sodium channel NaV1.1, which is highly expressed in GABAergic reticular thalamus (nRT) neurons as well as glutamatergic thalamocortical neurons. We hypothesized that NaV1.1 haploinsufficiency alters somatosensory corticothalamic circuit function through both intrinsic and synaptic mechanisms in nRT and thalamocortical neurons. Using Scn1a heterozygous mice of both sexes aged P25-P30, we discovered reduced excitability of nRT neurons and thalamocortical neurons in the ventral posterolateral (VPL) thalamus, while thalamocortical ventral posteromedial (VPM) neurons exhibited enhanced excitability. NaV1.1 haploinsufficiency enhanced GABAergic synaptic input and reduced glutamatergic input to VPL neurons, but not VPM neurons. In addition, glutamatergic input to nRT neurons was reduced in Scn1a heterozygous mice. These findings introduce alterations in glutamatergic synapse function and aberrant glutamatergic neuron excitability in the thalamus as disease mechanisms in DS, which has been widely considered a disease of GABAergic neurons. This work reveals additional complexity that expands current models of thalamic dysfunction in DS and identifies new components of corticothalamic circuitry as potential therapeutic targets.
The Journal of clinical endocrinology and metabolism
2022 Feb 11
Lecante, LL;Leverrier-Penna, S;Gicquel, T;Giton, F;Costet, N;Desdoits-Lethimonier, C;Lesné, L;Fromenty, B;Lavoué, V;Rolland, AD;Mazaud-Guittot, S;
PMID: 35147701 | DOI: 10.1210/clinem/dgac080
Acetaminophen (APAP, paracetamol) is widely used by pregnant women. Although long considered safe, growing evidence indicates that APAP is an endocrine disruptor since in utero exposure may be associated with a higher risk of male genital tract abnormalities. In rodents, fetal exposure has long-term effects on the reproductive function of female offspring. Human studies have also suggested harmful APAP exposure effects.Given that disruption of fetal ovarian development may impact women's reproductive health, we investigated the effects of APAP on fetal human ovaries in culture.Human ovarian fragments from 284 fetuses aged 7 to 12 developmental weeks (DW) were cultivated ex vivo for 7 days in the presence of human-relevant concentrations of APAP (10 -8 to 10 -3 M) or vehicle control.Outcomes included examination of postculture tissue morphology, cell viability, apoptosis, and quantification of hormones, APAP and APAP metabolites in conditioned culture media.APAP reduced the total cell number specifically in 10-12 DW ovaries induced cell death and decreased KI67-positive cell density independently of fetal age. APAP targeted sub-populations of germ cells and disrupted human fetal ovarian steroidogenesis, without affecting prostaglandin or inhibin B production. Human fetal ovaries were able to metabolize APAP.Our data indicate that APAP can impact first trimester human fetal ovarian development, especially during a 10-12 DW window of heightened sensitivity. Overall, APAP behaves as an endocrine disruptor in the fetal human ovary.
International journal of molecular sciences
2022 Jan 26
de Vallière, C;Cosin-Roger, J;Baebler, K;Schoepflin, A;Mamie, C;Mollet, M;Schuler, C;Bengs, S;Lang, S;Scharl, M;Seuwen, K;Ruiz, PA;Hausmann, M;Rogler, G;
PMID: 35163345 | DOI: 10.3390/ijms23031419
Local extracellular acidification occurs at sites of inflammation. Proton-sensing ovarian cancer G-protein-coupled receptor 1 (OGR1, also known as GPR68) responds to decreases in extracellular pH. Our previous studies show a role for OGR1 in the pathogenesis of mucosal inflammation, suggesting a link between tissue pH and immune responses. Additionally, pH-dependent signalling is associated with the progression of intestinal fibrosis. In this study, we aimed to investigate OGR1 expression and OGR1-mediated signalling in patients with inflammatory bowel disease (IBD). Our results show that OGR1 expression significantly increased in patients with IBD compared to non-IBD patients, as demonstrated by qPCR and immunohistochemistry (IHC). Paired samples from non-inflamed and inflamed intestinal areas of IBD patients showed stronger OGR1 IHC staining in inflamed mucosal segments compared to non-inflamed mucosa. IHC of human surgical samples revealed OGR1 expression in macrophages, granulocytes, endothelial cells, and fibroblasts. OGR1-dependent inositol phosphate (IP) production was significantly increased in CD14+ monocytes from IBD patients compared to healthy subjects. Primary human and murine fibroblasts exhibited OGR1-dependent IP formation, RhoA activation, F-actin, and stress fibre formation upon an acidic pH shift. OGR1 expression and signalling increases with IBD disease activity, suggesting an active role of OGR1 in the pathogenesis of IBD.
Biochemical pharmacology
2022 Feb 18
Kiguchi, N;Ding, H;Park, SH;Mabry, KM;Kishioka, S;Shiozawa, Y;Alfonso Romero-Sandoval, E;Peters, CM;Ko, MC;
PMID: 35189108 | DOI: 10.1016/j.bcp.2022.114972
Despite accumulating evidence in rodents, the functional role of neuromedin B (NMB) in regulating somatosensory systems in primate spinal cord is unknown. We aimed to compare the expression patterns of NMB and its receptor (NMBR) and the behavioral effects of intrathecal (i.t.) NMB with gastrin-releasing peptide (GRP) on itch or pain in non-human primates (NHPs). We used six adult rhesus monkeys. The mRNA or protein expressions of NMB, GRP, and their receptors were evaluated by quantitative reverse transcription polymerase chain reaction, immunohistochemistry, or in situ hybridization. We determined the behavioral effects of NMB or GRP via acute thermal nociception, capsaicin-induced thermal allodynia, and itch scratching response assays. NMB expression levels were greater than those of GRP in the dorsal root ganglia and spinal dorsal horn. Conversely, NMBR expression was significantly lower than GRP receptor (GRPR). I.t. NMB elicited only mild scratching responses, whereas GRP caused robust scratching responses. GRP- and NMB-elicited scratching responses were attenuated by GRPR (RC-3095) and NMBR (PD168368) antagonists, respectively. Moreover, i.t. NMB and GRP did not induce thermal hypersensitivity and GRPR and NMBR antagonists did not affect peripherally elicited thermal allodynia. Consistently, NMBR expression was low in both itch- and pain-responsive neurons in the spinal dorsal horn. Spinal NMB-NMBR system plays a minimal functional role in the neurotransmission of itch and pain in primates. Unlike the functional significance of the GRP-GRPR system in itch, drugs targeting the spinal NMB-NMBR system may not effectively alleviate non-NMBR-mediated itch.
Disease models & mechanisms
2022 Feb 02
Del-Pozo, J;Headon, DJ;Glover, JD;Azar, A;Schuepbach-Mallepell, S;Bhutta, MF;Riddell, J;Maxwell, S;Milne, E;Schneider, P;Cheeseman, M;
PMID: 35107126 | DOI: 10.1242/dmm.049034
In mice, rats, dogs and humans the growth and function of sebaceous glands and eyelid Meibomian glands depend on the ectodysplasin signalling pathway. Mutation of genes encoding the ligand EDA, its transmembrane receptor EDAR, and the intracellular signal transducer EDARADD leads to Hypohidrotic Ectodermal Dysplasia characterised by impaired development of teeth and hair as well as cutaneous glands. The rodent ear canal has a large auditory sebaceous gland, the Zymbal's gland, whose function in the health of the ear canal and tympanic membrane has not been determined. We report that the EDA deficient Tabby (EdaTa) mouse, the EDAR deficient mouse (EdarOVE1B/OVE1B) and the EDARADD deficient sparse and wavy hair rat (Edaraddswh/swh) have Zymbal's gland hypoplasia. EdaTa mice also have ear canal hypotrichosis and a 25% prevalence of otitis externa at P21. Treatment with agonist anti-EDAR antibodies rescues Zymbal's glands and ear canal pilosebaceous units. The aetiopathogenesis of otitis externa involves infection with Gram-positive cocci and dosing pregnant and lactating EdaTa females and pups with Enrofloxacin reduces the prevalence of otitis externa. We infer the deficit of sebum is the principal factor in predisposition to bacterial infection and the EdaTa mouse is a potentially useful microbial challenge model for human acute otitis externa, commonly known as swimmer's ear.
Laboratory investigation; a journal of technical methods and pathology
2022 Feb 15
Jamalzadeh, S;Häkkinen, A;Andersson, N;Huhtinen, K;Laury, A;Hietanen, S;Hynninen, J;Oikkonen, J;Carpén, O;Virtanen, A;Hautaniemi, S;
PMID: 35169222 | DOI: 10.1038/s41374-022-00743-5
RNA in situ hybridization (RNA-ISH) is a powerful spatial transcriptomics technology to characterize target RNA abundance and localization in individual cells. This allows analysis of tumor heterogeneity and expression localization, which are not readily obtainable through transcriptomic data analysis. RNA-ISH experiments produce large amounts of data and there is a need for automated analysis methods. Here we present QuantISH, a comprehensive open-source RNA-ISH image analysis pipeline that quantifies marker expressions in individual carcinoma, immune, and stromal cells on chromogenic or fluorescent in situ hybridization images. QuantISH is designed to be modular and can be adapted to various image and sample types and staining protocols. We show that in chromogenic RNA in situ hybridization images of high-grade serous carcinoma (HGSC) QuantISH cancer cell classification has high precision, and signal expression quantification is in line with visual assessment. We further demonstrate the power of QuantISH by showing that CCNE1 average expression and DDIT3 expression variability, as captured by the variability factor developed herein, act as candidate biomarkers in HGSC. Altogether, our results demonstrate that QuantISH can quantify RNA expression levels and their variability in carcinoma cells, and thus paves the way to utilize RNA-ISH technology.
Laboratory investigation; a journal of technical methods and pathology
2022 Feb 10
Kim, H;Lee, SB;Myung, JK;Park, JH;Park, E;Il Kim, D;Lee, C;Kim, Y;Park, CM;Kim, MB;Lim, GC;Jang, B;
PMID: 35145202 | DOI: 10.1038/s41374-022-00739-1
The histogenesis of pleomorphic adenoma (PA) of the salivary glands remains controversial. PAs are characterized by the transition of epithelial cells to spindled mesenchymal cells, known as epithelial-mesenchymal transition (EMT). The present study aimed to identify a major EMT-inducing transcription factor (EMT-TF) in PAs. Real-time PCR analysis of SNAIL, SLUG, ZEB1, and TWIST1 demonstrated that only SLUG was significantly upregulated in normal salivary glands and PAs. Combined in situ hybridization for SLUG and multiplex immunohistochemistry for CK19 and P63 revealed that SLUG was specifically expressed in the myoepithelial cells of normal salivary glands. In PAs, SLUG was expressed in neoplastic myoepithelial cells and stromal cells but not in the luminal cells lining the inner layers of tumor glands. SLUG expression showed no correlation with PLAG1 expression, and in vitro experiments demonstrated that PLAG1 suppression in primary cultured PA cells or PLAG1 overexpression in HEK 293 T cells did not affect SLUG levels, indicating that PLAG1 was not involved in the upregulation of SLUG in PAs. The suppression of SLUG expression in cultured PA cells resulted in a morphology change to a less elongated shape and attenuated tumor growth. In addition, SLUG downregulation led to increased E-cadherin and decreased N-cadherin and vimentin expression levels along with decreased migratory activity in cultured PA cells. These findings suggest that SLUG is a major TF that can induce EMT in PAs. In summary, SLUG is specifically and highly expressed in the myoepithelial cells and stromal cells of PAs and is a key regulator of EMT in PAs.
Journal of the American Heart Association
2022 Feb 15
Gao, H;Jin, Z;Tang, K;Ji, Y;Suarez, J;Suarez, JA;Cunha E Rocha, K;Zhang, D;Dillmann, WH;Mahata, SK;Ying, W;
PMID: 35112881 | DOI: 10.1161/JAHA.121.024561
Background Obesity is an established risk factor for hypertension. Although obesity-induced gut barrier breach leads to the leakage of various microbiota-derived products into host circulation and distal organs, the roles of microbiota in mediating the development of obesity-associated adrenomedullary disorders and hypertension have not been elucidated. We seek to explore the impacts of microbial DNA enrichment on inducing obesity-related adrenomedullary abnormalities and hypertension. Methods and Results Obesity was accompanied by remarkable bacterial DNA accumulation and elevated inflammation in the adrenal glands. Gut microbial DNA containing extracellular vesicles (mEVs) were readily leaked into the bloodstream and infiltrated into the adrenal glands in obese mice, causing microbial DNA enrichment. In lean wild-type mice, adrenal macrophages expressed CRIg (complement receptor of the immunoglobulin superfamily) that efficiently blocks the infiltration of gut mEVs. In contrast, the adrenal CRIg+ cell population was greatly decreased in obese mice. In lean CRIg-/- or C3-/- (complement component 3) mice intravenously injected with gut mEVs, adrenal microbial DNA accumulation elevated adrenal inflammation and norepinephrine secretion, concomitant with hypertension. In addition, microbial DNA promoted inflammatory responses and norepinephrine production in rat pheochromocytoma PC12 cells treated with gut mEVs. Depletion of microbial DNA cargo markedly blunted the effects of gut mEVs. We also validated that activation of cGAS (cyclic GMP-AMP synthase)/STING (cyclic GMP-AMP receptor stimulator of interferon genes) signaling is required for the ability of microbial DNA to trigger adrenomedullary dysfunctions in both in vivo and in vitro experiments. Restoring CRIg+ cells in obese mice decreased microbial DNA abundance, inflammation, and hypertension. Conclusions The leakage of gut mEVs leads to adrenal enrichment of microbial DNA that are pathogenic to induce obesity-associated adrenomedullary abnormalities and hypertension. Recovering the CRIg+ macrophage population attenuates obesity-induced adrenomedullary disorders.
Gynecologic oncology
2022 Feb 09
Liao, X;Xia, X;Su, W;Yan, H;Ma, Y;Xu, L;Luo, H;Liu, W;Yin, D;Zhang, WH;Chen, HN;Deng, Y;Ren, Z;Yu, Z;Liao, F;Chen, K;Cao, M;Zhang, Y;Zhang, W;Wang, W;Zhao, JN;Xu, H;Shu, Y;
PMID: 35151492 | DOI: 10.1016/j.ygyno.2022.01.036
Gastric-type cervical adenocarcinoma (GCA) is a rare and aggressive type of endocervical adenocarcinoma (ECA) with distinct histopathologic features and unfavorable treatment outcomes, but no genomic prognostic factor has been revealed. We aimed to systematically investigate the somatic alterations of GCA at genome-wide level and evaluate their prognostic value.We performed whole-exome sequencing (WES) on 25 pairs of tumor and matched normal samples to characterize the genomic features of Chinese patients with GCA and investigated their relations to histopathological characterizations and prognosis. The prognostic value of the genomic alterations was evaluated in a total of 58 GCA patients.Mutations were commonly observed in reported GCA-related driver genes, including TP53 (32%), CDKN2A (20%), SKT11 (20%), BRCA2 (12%), SMAD4 (12%), and ERBB2 (12%). Recurrent novel trunk mutations were also observed in PBRM1 (12%), FRMPD4 (12%), and NOP2 (8%) with high variant allele frequency. Moreover, enrichment of the APOBEC signature was attributed to frequent gain of somatic copy number alteration (SCNA) of APOBEC3B (20%), which perfectly matched the nuclear-positive staining of APOBEC3B through immunohistochemistry. In contrast, APOBEC3B alteration was absent in patients with conventional type of ECA (N = 52). Notably, positive APOBEC3B was consistently enriched in patients with favorable prognosis in both the discovery cohort and an additional 33 GCA patients, thus indicating a significant association with lower relapse risk of GCA independent of cancer stage (P = 0.02).Our results can aid understanding of the molecular basis of GCA in the Chinese population by providing genomic profiles and highlighting the potential prognostic value of APOBEC3B for GCA through routine clinical IHC.
Journal of immunology (Baltimore, Md. : 1950)
2022 Feb 18
Manivasagam, S;Williams, JL;Vollmer, LL;Bollman, B;Bartleson, JM;Ai, S;Wu, GF;Klein, RS;
PMID: 35181638 | DOI: 10.4049/jimmunol.2101041
Type III IFNs (IFNLs) are newly discovered cytokines, acting at epithelial and other barriers, that exert immunomodulatory functions in addition to their primary roles in antiviral defense. In this study, we define a role for IFNLs in maintaining autoreactive T cell effector function and limiting recovery in a murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis. Genetic or Ab-based neutralization of the IFNL receptor (IFNLR) resulted in lack of disease maintenance during experimental autoimmune encephalomyelitis, with loss of CNS Th1 effector responses and limited axonal injury. Phenotypic effects of IFNLR signaling were traced to increased APC function, with associated increase in T cell production of IFN-γ and GM-CSF. Consistent with this, IFNL levels within lesions of CNS tissues derived from patients with MS were elevated compared with MS normal-appearing white matter. Furthermore, expression of IFNLR was selectively elevated in MS active lesions compared with inactive lesions or normal-appearing white matter. These findings suggest IFNL signaling as a potential therapeutic target to prevent chronic autoimmune neuroinflammation.
Biochemical Society transactions
2022 Feb 28
Jin, S;Ramos, R;
PMID: 35191953 | DOI: 10.1042/BST20210863
Tissue development and homeostasis require coordinated cell-cell communication. Recent advances in single-cell sequencing technologies have emerged as a revolutionary method to reveal cellular heterogeneity with unprecedented resolution. This offers a great opportunity to explore cell-cell communication in tissues systematically and comprehensively, and to further identify signaling mechanisms driving cell fate decisions and shaping tissue phenotypes. Using gene expression information from single-cell transcriptomics, several computational tools have been developed for inferring cell-cell communication, greatly facilitating analysis and interpretation. However, in single-cell transcriptomics, spatial information of cells is inherently lost. Given that most cell signaling events occur within a limited distance in tissues, incorporating spatial information into cell-cell communication analysis is critical for understanding tissue organization and function. Spatial transcriptomics provides spatial location of cell subsets along with their gene expression, leading to new directions for leveraging spatial information to develop computational approaches for cell-cell communication inference and analysis. These computational approaches have been successfully applied to uncover previously unrecognized mechanisms of intercellular communication within various contexts and across organ systems, including the skin, a formidable model to study mechanisms of cell-cell communication due to the complex interactions between the different cell populations that comprise it. Here, we review emergent cell-cell communication inference tools using single-cell transcriptomics and spatial transcriptomics, and highlight the biological insights gained by applying these computational tools to exploring cellular communication in skin development, homeostasis, disease and aging, as well as discuss future potential research avenues.
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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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