Somatostatin regulates central clock function and circadian responses to light

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

2023 May 02

Joye, DAM;Rohr, KE;Suenkens, K;Wuorinen, A;Inda, T;Arzbecker, M;Mueller, E;Huber, A;Pancholi, H;Blackmore, MG;Carmona-Alcocer, V;Evans, JA;
PMID: 37098068 | DOI: 10.1073/pnas.2216820120

Daily and annual changes in light are processed by central clock circuits that control the timing of behavior and physiology. The suprachiasmatic nucleus (SCN) in the anterior hypothalamus processes daily photic inputs and encodes changes in day length (i.e., photoperiod), but the SCN circuits that regulate circadian and photoperiodic responses to light remain unclear. Somatostatin (SST) expression in the hypothalamus is modulated by photoperiod, but the role of SST in SCN responses to light has not been examined. Our results indicate that SST signaling regulates daily rhythms in behavior and SCN function in a manner influenced by sex. First, we use cell-fate mapping to provide evidence that SST in the SCN is regulated by light via de novo Sst activation. Next, we demonstrate that Sst -/- mice display enhanced circadian responses to light, with increased behavioral plasticity to photoperiod, jetlag, and constant light conditions. Notably, lack of Sst -/- eliminated sex differences in photic responses due to increased plasticity in males, suggesting that SST interacts with clock circuits that process light differently in each sex. Sst -/- mice also displayed an increase in the number of retinorecipient neurons in the SCN core, which express a type of SST receptor capable of resetting the molecular clock. Last, we show that lack of SST signaling modulates central clock function by influencing SCN photoperiodic encoding, network after-effects, and intercellular synchrony in a sex-specific manner. Collectively, these results provide insight into peptide signaling mechanisms that regulate central clock function and its response to light.

Chronic demyelination of rabbit lesions is attributable to failed oligodendrocyte progenitor cell repopulation

Glia

2022 Dec 20

Cooper, JJM;Polanco, JJ;Saraswat, D;Peirick, JJ;Seidl, A;Li, Y;Ma, D;Sim, FJ;
PMID: 36537341 | DOI: 10.1002/glia.24324

The failure of remyelination in the human CNS contributes to axonal injury and disease progression in multiple sclerosis (MS). In contrast to regions of chronic demyelination in the human brain, remyelination in murine models is preceded by abundant oligodendrocyte progenitor cell (OPC) repopulation, such that OPC density within regions of demyelination far exceeds that of normal white matter (NWM). As such, we hypothesized that efficient OPC repopulation was a prerequisite of successful remyelination, and that increased lesion volume may contribute to the failure of OPC repopulation in human brain. In this study, we characterized the pattern of OPC activation and proliferation following induction of lysolecithin-induced chronic demyelination in adult rabbits. The density of OPCs never exceeded that of NWM and oligodendrocyte density did not recover even at 6 months post-injection. Rabbit OPC recruitment in large lesions was further characterized by chronic Sox2 expression in OPCs located in the lesion core and upregulation of quiescence-associated Prrx1 mRNA at the lesion border. Surprisingly, when small rabbit lesions of equivalent size to mouse were induced, they too exhibited reduced OPC repopulation. However, small lesions were distinct from large lesions as they displayed an almost complete lack of OPC proliferation following demyelination. These differences in the response to demyelination suggest that both volume dependent and species-specific mechanisms are critical in the regulation of OPC proliferation and lesion repopulation and suggest that alternate models will be necessary to fully understand the mechanisms that contribute to failed remyelination in MS.

Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15

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

2021 Jul 06

Cimino, I;Kim, H;Tung, YCL;Pedersen, K;Rimmington, D;Tadross, JA;Kohnke, SN;Neves-Costa, A;Barros, A;Joaquim, S;Bennett, D;Melvin, A;Lockhart, SM;Rostron, AJ;Scott, J;Liu, H;Burling, K;Barker, P;Clatworthy, MR;Lee, EC;Simpson, AJ;Yeo, GSH;Moita, LF;Bence, KK;Jørgensen, SB;Coll, AP;Breen, DM;O'Rahilly, S;
PMID: 34187898 | DOI: 10.1073/pnas.2106868118

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15 -/- mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

Investigating post-transcriptional mechanisms of neuropathic pain

The Journal of Pain

2021 May 01

Li, X;Jeon, S;Eadara, S;Onuchukwu, U;Caterina, M;Meffert, M;
| DOI: 10.1016/j.jpain.2021.03.010

Neuropathic pain is a chronic condition which can arise following damage to the somatosensory system and often involves both hyperalgesia and allodynia. The molecular mechanisms of neuropathic pain remain incompletely understood but require enduring alterations in specific gene program expression and protein synthesis affecting neuronal signaling and excitability. We investigate the roles of non-coding RNA regulatory pathways in impacting hyperalgesia and determining the mRNA complement recruited during the protein synthesis response in neuropathic pain. Nerve injury alters the expression of many miRNAs, including the highly conserved let-7 family miRNAs, which repress pro-growth mRNAs and are implicated in axon growth, neuronal plasticity, and brain circuit development. The Lin28 RNA binding protein can prevent maturation of let-7 precursor RNAs; consequently, increased Lin28 signaling promotes pro-growth gene expression. The regulation and potential roles role of Lin28/let-7 pathway in neuropathic pain remain largely unexplored. Using spared nerve injury (SNI) mouse models of neuropathic pain, we find in preliminary data that Lin28a loss of function in sensory neuron populations can result in a deficit in mechanical hypersensitivity post-surgery. In SNI and sciatic nerve transection (SNT) mouse models, we evaluate molecular mechanisms underlying pain using single molecule detection and genetic manipulation. A sensitive RNA imaging assays, RNAScope in situ hybridization (ISH), is used to amplify single RNA target signals in fixed tissues to allow mapping of the spatiotemporal patterns and cell type specificity of changes in non-coding RNA regulatory pathways. Digital PCR is used to provide sensitive and quantitative validation. We find lin28 mRNA level are elevated in injured dorsal root ganglion cells, injured sciatic nerves and their surrounding Schwann cells at 3 days post SNI and SNT surgery accordingly.

In Situ Hybridization (ISH) Combined with Immunocytochemistry (ICC) Co-detection of Phosphorylated EGFR in A431 Cultured Cells

Methods in molecular biology (Clifton, N.J.)

2022 Dec 13

Hagen, J;Oliver, A;Kalyuzhny, AE;
PMID: 36513933 | DOI: 10.1007/978-1-0716-2811-9_13

Antibodies have been commonly used to study protein phosphorylation since the first phospho-specific antibody was described in 1981. Antibodies can be developed so that they specifically recognize phosphorylated areas of particular proteins. In situ hybridization (ISH) is the technique where specific RNA or DNA molecules can be detected in a single cell without the need for antibodies. Using ACD's integrated Co-Detection Workflow (ICW), we have developed a protocol to use phospho-specific antibodies in combination with ISH to show co-localization of EGFR mRNA and EGFR proteins phosphorylated at different sites in tumor cells. Our protocol has been used for multiplexing Y1086 phosphorylated EGFR, Y1068 phosphorylated EGFR, and EGFR RNA in A431 human epidermoid carcinoma cells.

Spatial molecular and cellular determinants of STAT3 activation in liver fibrosis progression in non-alcoholic fatty liver disease

JHEP Reports

2022 Nov 01

Jiao, J;Sanchez, J;Saldarriaga, O;Solis, L;Tweardy, D;Maru, D;Stevenson, H;Beretta, L;
| DOI: 10.1016/j.jhepr.2022.100628

Background & Aims The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is increasing. Subjects with NASH often develop liver fibrosis and advanced liver fibrosis is the main determinant of mortality in NASH patients. We and others have reported that STAT3 contributes to liver fibrosis and hepatocellular carcinoma in mice. Methods Here, we explored whether STAT3 activation in hepatocytes and in non-hepatocytes areas, measured by phospho-STAT3 (pSTAT3), is associated with liver fibrosis progression in 133 patients with NAFLD. We further characterized the molecular and cellular determinants of STAT3 activation by integrating spatial distribution and transcriptomic changes in fibrotic NAFLD liver. Results pSTAT3 scores in non-hepatocytes areas progressively increased with fibrosis severity (r=0.53, p

Prevalence of Human Papilloma Virus Infection in Bladder Cancer: A Systematic Review

Diagnostics (Basel, Switzerland)

2022 Jul 20

Muresu, N;Di Lorenzo, B;Saderi, L;Sechi, I;Del Rio, A;Piana, A;Sotgiu, G;
PMID: 35885662 | DOI: 10.3390/diagnostics12071759

The etiology of bladder cancer is known to be associated with behavioral and environmental factors. Moreover, several studies suggested a potential role of HPV infection in the pathogenesis with controversial results. A systematic review was conducted to assess the role of HPV. A total of 46 articles that reported the prevalence of HPV infection in squamous (SCC), urothelial (UC), and transitional cell carcinomas (TCC) were selected. A pooled prevalence of 19% was found, with a significant difference in SCC that was mainly driven by HPV-16. Moreover, infection prevalence in case-control studies showed a higher risk of bladder cancer in HPV-positive cases (OR: 7.84; p-value < 0.00001). The results may suggest an etiologic role of HPV in bladder cancer. HPV vaccine administration in both sexes could be key to prevent the infection caused by high-risk genotypes.

IL-38 Ablation Reduces Local Inflammation and Disease Severity in Experimental Autoimmune Encephalomyelitis

Journal of immunology (Baltimore, Md. : 1950)

2021 Mar 01

Huard, A;Do, HN;Frank, AC;Sirait-Fischer, E;Fuhrmann, D;Hofmann, MCJ;Raue, R;Palmer, G;Brüne, B;de Bruin, N;Weigert, A;
PMID: 33504620 | DOI: 10.4049/jimmunol.2000923

IL-38 is an IL-1 family receptor antagonist that restricts IL-17-driven inflammation by limiting cytokine production from macrophages and T cells. In the current study, we aimed to explore its role in experimental autoimmune encephalomyelitis in mice, which is, among others, driven by IL-17. Unexpectedly, IL-38-deficient mice showed strongly reduced clinical scores and histological markers of experimental autoimmune encephalomyelitis. This was accompanied by reduced inflammatory cell infiltrates, including macrophages and T cells, as well as reduced expression of inflammatory markers in the spinal cord. IL-38 was highly expressed by infiltrating macrophages in the spinal cord, and in vitro activated IL-38-deficient bone marrow-derived macrophages showed reduced expression of inflammatory markers, accompanied by altered cellular metabolism. These data suggest an alternative cell-intrinsic role of IL-38 to promote inflammation in the CNS.

Analysis of gene expression of prostaglandin EP4 receptor in canine osteosarcoma

Canadian journal of veterinary research = Revue canadienne de recherche veterinaire

2021 Jan 01

Musser, ML;Viall, AK;Phillips, RL;Hostetter, JM;Johannes, CM;
PMID: 33390656

In many human cancers, the expression of the prostaglandin receptor EP4 (EP4R) is associated with the development of malignancy and a poor prognosis. The expression of EP4R has not yet been evaluated in canine tumors. The objective of this study was to characterize the messenger RNA (mRNA) expression of EP4R in canine osteosarcoma (OSA). Gene expression of EP4R was evaluated using RNA in-situ hybridization (RNAscope). In all canine OSA samples evaluated, strong universal positive expression of EP4R was identified. Gene expression was significantly higher in OSA tissue samples than in normal nasal turbinate bone, possibly implicating EP4R in the pathogenesis of canine OSA.

Whole Exome Sequencing Study Suggests an Impact of FANCA, CDH1 and VEGFA Genes on Diffuse Gastric Cancer Development

Genes

2023 Jan 21

Nurgalieva, A;Galliamova, L;Ekomasova, N;Yankina, M;Sakaeva, D;Valiev, R;Prokofyeva, D;Dzhaubermezov, M;Fedorova, Y;Khusnutdinov, S;Khusnutdinova, E;
PMID: 36833207 | DOI: 10.3390/genes14020280

Gastric cancer (GC) is one of the most common cancer types in the world with a high mortality rate. Hereditary predisposition for GC is not fully elucidated so far. The aim of this study was identification of possible new candidate genes, associated with the increased risk of gastric cancer development. Whole exome sequencing (WES) was performed on 18 DNA samples from adenocarcinoma specimens and non-tumor-bearing healthy stomach tissue from the same patient. Three pathogenic variants were identified: c.1320+1G>A in the CDH1 gene and c.27_28insCCCAGCCCCAGCTACCA (p.Ala9fs) of the VEGFA gene were found only in the tumor tissue, whereas c.G1874C (p.Cys625Ser) in the FANCA gene was found in both the tumor and normal tissue. These changes were found only in patients with diffuse gastric cancer and were absent in the DNA of healthy donors.

Imaging mass cytometry: High-dimensional and single-cell perspectives on the microenvironment of solid tumours

Progress in biophysics and molecular biology

2022 Nov 01

Liu, Z;Xun, J;Liu, S;Wang, B;Zhang, A;Zhang, L;Wang, X;Zhang, Q;
PMID: 36252872 | DOI: 10.1016/j.pbiomolbio.2022.10.003

Imaging mass cytometry (IMC) is a new technology integrating mass spectrometry, high-resolution laser ablation and immunohistochemistry/cytochemistry. A unique high-dimensional perspective comprehensively and accurately depicts the complex interaction of phenotype, signalling pathway and tumour microenvironment and is widely used in solid tumours. However, the application scenarios of IMC in basic medicine and clinical research in solid tumours lack systematic introduction and classification. This paper reviews the application of IMC in depicting the panorama of the tumour microenvironment, revealing tumour spatial heterogeneity, clarifying tumour pharmacological mechanisms, assisting in new drug development, and dynamically evaluating the efficacy of immunotherapy in solid tumours.

Spatially resolved transcriptomics and the kidney: many opportunities

Kidney international

2022 Jul 02

Dixon, EE;Wu, H;Sulvarán-Guel, E;Guo, J;Humphreys, BD;
PMID: 35788360 | DOI: 10.1016/j.kint.2022.06.011

Defining changes in gene expression during health and disease is critical for the understanding of human physiology. In recent years, single-cell/nuclei RNA sequencing (sc/snRNAseq) has revolutionized the definition and discovery of cell types and states as well as the interpretation of organ- and cell-type-specific signaling pathways. However, these advances require tissue dissociation to the level of the single cell or single nuclei level. Spatially resolved transcriptomics (SrT) now provides a platform to overcome this barrier in understanding the physiological contexts of gene expression and cellular microenvironment changes in development and disease. Some of these transcriptomic tools allow for high-resolution mapping of hundreds of genes simultaneously in cellular and subcellular compartments. Other tools offer genome depth mapping but at lower resolution. We review advances in SrT, considerations for using SrT in your own research, and applications for kidney biology.

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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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