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Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

Molecular psychiatry

2021 Jul 12

Kim, HD;Wei, J;Call, T;Quintus, NT;Summers, AJ;Carotenuto, S;Johnson, R;Ma, X;Xu, C;Park, JG;Qiu, S;Ferguson, D;
PMID: 34253865 | DOI: 10.1038/s41380-021-01217-8

Depression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

Specialized endothelial tip cells guide neuroretina vascularization and blood-retina-barrier formation

Developmental cell

2021 Jul 12

Zarkada, G;Howard, JP;Xiao, X;Park, H;Bizou, M;Leclerc, S;Künzel, SE;Boisseau, B;Li, J;Cagnone, G;Joyal, JS;Andelfinger, G;Eichmann, A;Dubrac, A;
PMID: 34273276 | DOI: 10.1016/j.devcel.2021.06.021

Endothelial tip cells guiding tissue vascularization are primary targets for angiogenic therapies. Whether tip cells require differential signals to develop their complex branching patterns remained unknown. Here, we show that diving tip cells invading the mouse neuroretina (D-tip cells) are distinct from tip cells guiding the superficial retinal vascular plexus (S-tip cells). D-tip cells have a unique transcriptional signature, including high TGF-β signaling, and they begin to acquire blood-retina barrier properties. Endothelial deletion of TGF-β receptor I (Alk5) inhibits D-tip cell identity acquisition and deep vascular plexus formation. Loss of endothelial ALK5, but not of the canonical SMAD effectors, leads to aberrant contractile pericyte differentiation and hemorrhagic vascular malformations. Oxygen-induced retinopathy vasculature exhibits S-like tip cells, and Alk5 deletion impedes retina revascularization. Our data reveal stage-specific tip cell heterogeneity as a requirement for retinal vascular development and suggest that non-canonical-TGF-β signaling could improve retinal revascularization and neural function in ischemic retinopathy.

OMICs, Epigenetics, and Genome Editing Techniques for Food and Nutritional Security

Plants

2021 Jul 12

Gogolev, Y;Ahmar, S;Akpinar, B;Budak, H;Kiryushkin, A;Gorshkov, V;Hensel, G;Demchenko, K;Kovalchuk, I;Mora-Poblete, F;Muslu, T;Tsers, I;Yadav, N;Korzun, V;
| DOI: 10.3390/plants10071423

The incredible success of crop breeding and agricultural innovation in the last century greatly contributed to the Green Revolution, which significantly increased yields and ensures food security, despite the population explosion. However, new challenges such as rapid climate change, deteriorating soil, and the accumulation of pollutants require much faster responses and more effective solutions that cannot be achieved through traditional breeding. Further prospects for increasing the efficiency of agriculture are undoubtedly associated with the inclusion in the breeding strategy of new knowledge obtained using high-throughput technologies and new tools in the future to ensure the design of new plant genomes and predict the desired phenotype. This article provides an overview of the current state of research in these areas, as well as the study of soil and plant microbiomes, and the prospective use of their potential in a new field of microbiome engineering. In terms of genomic and phenomic predictions, we also propose an integrated approach that combines high-density genotyping and high-throughput phenotyping techniques, which can improve the prediction accuracy of quantitative traits in crop species.

Dysregulation of PI3K/Akt/PTEN Pathway in Canine Mammary Tumor

Animals

2021 Jul 12

Kim, S;Seung, B;Cho, S;Lim, H;Bae, M;Sur, J;
| DOI: 10.3390/ani11072079

The PI3K/Akt/PTEN axis is one of the most important signaling pathways in tumorigenesis. Recently, mutation of PIK3CA has been highlighted due to the similarities of mutational hotspots in both dogs and humans. PIK3CA H1047R (c.3140A > G) has been discovered as the most common mutational hot spot in canine mammary tumor in recent studies, while the feature of PIK3CA-mutated canine mammary tumor is obscure. Methods: A total of 83 mammary samples classified as normal (n = 13), adenoma (n = 25), low-grade carcinoma (n = 21), and high-grade carcinoma (n = 24) were included in this study. Genomic DNA from each sample was extracted, amplified by conventional PCR, and analyzed through Sanger sequencing. Analysis for the expression of PIK3CA, Akt, p-Akt, and PTEN was performed by immunohistochemistry, and of Akt2 by RNA in situ hybridization. Results: PIK3CA H1047R mutation was detected in 14.3% (10/70) of tumor samples. Dysregulation of p-Akt, Akt2, and PTEN was observed in mammary tumor samples, but only PTEN dysregulation was associated with PIK3CA H1047R mutation. Conclusions: The present study showed that dysregulation of components in the PI3K/Akt/PTEN pathway is a feature of canine mammary tumors, but this dysregulation is not directly correlated to the PIK3CA H1047R mutation except for PTEN expression.

Prostaglandin EP4 receptor mRNA expression in canine lymphoma

Veterinary and comparative oncology

2021 Jul 11

Musser, ML;Viall, AK;Phillips, RL;Fasina, O;Johannes, CM;
PMID: 34250711 | DOI: 10.1111/vco.12753

Canine lymphoma (LSA) is a diverse, aggressive malignancy initiated by a variety of factors. Understanding those factors could help identify potential treatment options. Chronic inflammation drives lymphoma in human medicine and is suspected to play a role in veterinary medicine. The exact mechanisms, however, have not been elucidated. Upregulation of the cyclooxygenase enzymes, and subsequently prostaglandins, potentially play a stimulatory role. Prostaglandins work through one of four EP receptors (EP1-EP4) and the effects mediated through EP4R specifically are thought to be the primary drivers of cancer development. In human T-cell LSA, overexpression of EP4R has been found and appears to protect LSA cells from apoptosis. The role of EP4R in human B-cell LSA is more nuanced. This study aims to evaluate the mRNA expression of the EP4R gene (ptger4) in canine B-cell and T-cell LSA. Archived canine lymph nodes with histologically confirmed B-cell and T-cell LSA, and reactive lymph nodes, were evaluated for EP4R mRNA expression using a novel RNA in situ hybridization technique (RNAscope). Quantification of RNAscope signals was completed with an advanced digital pathology image analysis system (HALO). Results were reported as copy number, H-score, and percent tumour cell expression of EP4R mRNA. All reactive, B-cell LSA, and T-cell LSA lymph nodes expressed EP4R mRNA. The mRNA copy number, H-score, and percent tumour cell expression of EP4R were higher in B-cell (p < .003) and T-cell (p < .001) LSA samples compared to reactive lymph node samples. There were no differences between B-cell LSA and T-cell LSA.

Nox4 Maintains Blood Pressure during Low Sodium Diet

Antioxidants

2021 Jul 10

Rezende, F;Malacarne, P;Müller, N;Rathkolb, B;Hrabě de Angelis, M;Schröder, K;P Brandes, R;
| DOI: 10.3390/antiox10071103

The NADPH oxidase Nox4 is a hydrogen peroxide (H2O2)-producing enzyme, with the highest expression in the kidney. As the kidney is involved in volume and blood pressure control through sodium handling, we set out to determine the impact of a low sodium diet on these parameters in WT and Nox4-/- mice. Nox4 expression in the murine kidney was restricted to the proximal tubule. Nevertheless, low-sodium-induced weight loss and sodium sparing function was similar in WT and Nox4-/- mice, disputing an important function of renal Nox4 in sodium handling. In contrast, a low sodium diet resulted in a reduction in systolic blood pressure in Nox4-/- as compared to WT mice. This was associated with a selectively lower pressure to heart-rate ratio, as well as heart to body weight ratio. In general, a low sodium diet leads to activation of sympathetic tone and the renin angiotensin system, which subsequently increases peripheral resistance. Our observations suggest that the control by this system is attenuated in Nox4-/- mice, resulting in lower blood pressure in response to low sodium.

IL-6 expression helps distinguish Castleman\'s disease from IgG4-related disease in the lung

BMC pulmonary medicine

2021 Jul 10

Kinugawa, Y;Uehara, T;Iwaya, M;Asaka, S;Kobayashi, S;Nakajima, T;Komatsu, M;Yasuo, M;Yamamoto, H;Ota, H;
PMID: 34246246 | DOI: 10.1186/s12890-021-01603-6

It is difficult to distinguish between multicentric Castleman's disease (MCD) and IgG4-related lung disease (IgG4-LD), an IgG4-related disease (IgG4-RD) in the lung.We focused on IL-6, which is elevated in MCD, to distinguish between MCD and IgG4-LD by RNAscope, a highly sensitive RNA in situ method. Six cases of MCD and four cases of IgG4-LD were selected.In all cases of MCD and IgG4-LD, 10 or more IgG4-positive cells were found in one high-power field. All MCD cases were inconsistent with the pathological IgG4-related comprehensive diagnostic criteria, but 2 of 6 cases had an IgG4/IgG ratio greater than 40%. In all IgG4-LD cases, histological features were consistent with the pathological IgG4-RD comprehensive diagnostic criteria. IL-6 expression was observed in all MCD and IgG4-LD cases except for one IgG4-LD biopsy. IL-6-expressing cells were mainly identified in the stroma. Sites of IL-6 expression were not characteristic and were sparse. IL-6 expression tended to be higher in MCD compared with IgG4-LD. A positive correlation was found between the IL-6 H-score and serum IL-6 level.Differences in IL-6 expression may help distinguish between MCD and IgG4-LD. In addition, the presence of high IL-6 levels may help elucidate the pathological mechanisms of IgG4-LD.

An isoform of Dicer protects mammalian stem cells against multiple RNA viruses

Science (New York, N.Y.)

2021 Jul 09

Poirier, EZ;Buck, MD;Chakravarty, P;Carvalho, J;Frederico, B;Cardoso, A;Healy, L;Ulferts, R;Beale, R;Reis E Sousa, C;
PMID: 34244417 | DOI: 10.1126/science.abg2264

In mammals, early resistance to viruses relies on interferons, which protect differentiated cells but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialized Dicer protein that cleaves viral double-stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. We identified an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses-including Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity, in which different cell-intrinsic antiviral pathways can be tailored to the differentiation status of cells.

GPR151 in nociceptors modulates neuropathic pain via regulating P2X3 function and microglial activation

Brain : a journal of neurology

2021 Jul 09

Xia, LP;Luo, H;Ma, Q;Xie, YK;Li, W;Hu, H;Xu, ZZ;
PMID: 34244727 | DOI: 10.1093/brain/awab245

Neuropathic pain is a major health problem that affects up to 7-10% of the population worldwide. Currently, neuropathic pain is difficult to treat due to its elusive mechanisms. Here we report that orphan G protein-coupled receptor 151 (GPR151) in nociceptive sensory neurons controls neuropathic pain induced by nerve injury. GPR151 was mainly expressed in nonpeptidergic C-fiber dorsal root ganglion (DRG) neurons and highly upregulated after nerve injury. Importantly, conditional knockout of Gpr151 in adult nociceptive sensory neurons significantly alleviated chronic constriction injury (CCI)-induced neuropathic pain-like behavior but did not affect basal nociception. Moreover, GPR151 in DRG neurons was required for CCI-induced neuronal hyperexcitability and upregulation of colony-stimulating factor 1 (CSF1), which is necessary for microglial activation in the spinal cord after nerve injury. Mechanistically, GPR151 coupled with P2X3 ion channels and promoted their functional activities in neuropathic pain-like hypersensitivity. Knockout of Gpr151 suppressed P2X3-mediated calcium elevation and spontaneous pain behavior in CCI mice. Conversely, overexpression of Gpr151 significantly enhanced P2X3-mediated calcium elevation and DRG neuronal excitability. Furthermore, knockdown of P2X3 in DRGs reversed CCI-induced CSF1 upregulation, spinal microglial activation, and neuropathic pain-like behavior. Finally, the co-expression of GPR151 and P2X3 was confirmed in small-diameter human DRG neurons, indicating the clinical relevance of our findings. Together, our results suggest that GPR151 in nociceptive DRG neurons plays a key role in the pathogenesis of neuropathic pain and could be a potential target for treating neuropathic pain.

Pancreatic Cancer Chemotherapy Is Potentiated by Induction of Tertiary Lymphoid Structures in Mice

Cellular and molecular gastroenterology and hepatology

2021 Jul 09

Delvecchio, FR;Fincham, REA;Spear, S;Clear, A;Roy-Luzarraga, M;Balkwill, FR;Gribben, JG;Bombardieri, M;Hodivala-Dilke, K;Capasso, M;Kocher, HM;
PMID: 34252585 | DOI: 10.1016/j.jcmgh.2021.06.023

The presence of tertiary lymphoid structures (TLSs) may confer survival benefit to patients with pancreatic ductal adenocarcinoma (PDAC), in an otherwise immunologically inert malignancy. Yet, the precise role in PDAC has not been elucidated. Here, we aim to investigate the structure and role of TLSs in human and murine pancreatic cancer.Multicolor immunofluorescence and immunohistochemistry were used to fully characterize TLSs in human and murine (transgenic [KPC (KrasG12D, p53R172H, Pdx-1-Cre)] and orthotopic) pancreatic cancer. An orthotopic murine model was developed to study the development of TLSs and the effect of the combined chemotherapy and immunotherapy on tumor growth.Mature, functional TLSs are not ubiquitous in human PDAC and KPC murine cancers and are absent in the orthotopic murine model. TLS formation can be induced in the orthotopic model of PDAC after intratumoral injection of lymphoid chemokines (CXCL13/CCL21). Coadministration of systemic chemotherapy (gemcitabine) and intratumoral lymphoid chemokines into orthotopic tumors altered immune cell infiltration ,facilitating TLS induction and potentiating antitumor activity of chemotherapy. This resulted in significant tumor reduction, an effect not achieved by either treatment alone. Antitumor activity seen after TLS induction is associated with B cell-mediated dendritic cell activation.This study provides supportive evidence that TLS induction may potentiate the antitumor activity of chemotherapy in a murine model of PDAC. A detailed understanding of TLS kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immune-oncology.

A Contemporary Systematic Review on Repartition of HPV-Positivity in Oropharyngeal Cancer Worldwide

Viruses

2021 Jul 09

Carlander, A;Jakobsen, K;Bendtsen, S;Garset-Zamani, M;Lynggaard, C;Jensen, J;Grønhøj, C;Buchwald, C;
| DOI: 10.3390/v13071326

Significant variation in human papillomavirus (HPV) prevalence in oropharyngeal squamous cell carcinoma (OPSCC) across countries ranging from 11% in Brazil to 74% in New Zealand has been reported earlier. The aim of this study was to systematically review the most recently published studies on the occurrence of HPV in OPSCC globally. PubMed and Embase were systematically searched for articles assessing the occurrence of HPV+ OPSCC published between January 2016 and May 2021. Studies with a study period including 2015 and the following years were included. Both HPV DNA and/or p16 were accepted as indicators of HPV+ OPSCC. 31 studies were enrolled comprising 49,564 patients with OPSCC (range 12-42,024 patients per study) from 26 different countries covering all continents. The lowest occurrences of HPV+ OPSCC were observed in India (0%) and Spain (10%) and the highest occurrences were observed in Lebanon (85%) and Sweden (70%). We observed great variation in HPV prevalence in OPSCC worldwide varying from 0% to 85%. The highest occurrences of HPV+ OPSCC were found in general in Northern European countries, USA, Lebanon, China, and South Korea. We observed a trend of increase in HPV-positivity, indicating a mounting burden of HPV+ OPSCC.

EXPRESS: Phosphoproteomic Analysis of Lung tissue from Patients with Pulmonary Arterial Hypertension

Pulmonary Circulation

2021 Jul 09

Sitapara, R;Lam, T;Gandjeva, A;Tuder, R;Zisman, L;
| DOI: 10.1177/20458940211031109

Pulmonary Arterial Hypertension (PAH) is a rare disorder associated with high morbidity and mortality despite currently available treatments. We compared the phosphoproteome of lung tissue from subjects with iPAH obtained at the time of lung transplant with control lung tissue. The mass spectrometry-based analysis found 60,428 phosphopeptide features from which 6622 proteins were identified. Within the subset of identified proteins there were 1234 phosphopeptides with q<0.05, many of which are involved in immune regulation, angiogenesis, and cell proliferation. Most notably there was a marked relative increase in phosphorylated (S378) IKZF3 (Aiolos), a zinc finger transcription factor that plays a key role in lymphocyte regulation. In vitro phosphorylation assays indicated that GSK3 alpha and/or GSK3 beta could phosphorylate IKZF3 at S378. Western blot analysis demonstrated increased pIKZF3 in iPAH lungs compared to controls. Immunohistochemistry demonstrated phosphorylated IKZF3 in lymphocytes surrounding severely hypertrophied pulmonary arterioles. In situ hybrization showed gene expression in lymphocyte aggregates in PAH samples. A BCL2 reporter assay showed that IKZF3 increased BCL2 promoter activity and demonstrated the potential role of phosphorylation of IKZF3 on the regulation of BCL mediated transcription. Kinase network analysis demonstrated potentially important regulatory roles of casein kinase 2, CDK1, MAPKs, and PRKs in iPAH. Bioinformatic analysis demonstrated enrichment of Rho GTPase signaling and the potential importance of PRKG. In conclusion, this unbiased phosphoproteomic analysis demonstrated several novel targets regulated by kinase networks in iPAH, and reinforced the potential role of immune regulation in the pathogenesis of iPAH. The identified up and down-regulated phosphoproteins have potential to serve as biomarkers for PAH and to provide new insights for therapeutic strategies.

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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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