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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world with a high incidence and has become one of the most malignant cancers worldwide. Its clinical treatment mainly includes surgical intervention, chemotherapy, and immunotherapy, with poor curative effect and prognosis. In recent years, with the development of basic research, it has been revealed that protein tyrosine phosphatase receptor-type O (PTPRO) plays an important role in the pathogenesis of hepatocellular carcinoma. Protein tyrosine phosphatase receptor-type O is a new type of protein tyrosine phosphatase, which has been proven to inhibit oncoprotein. In this paper, the potential mechanism of protein tyrosine phosphatase receptor -type O in the progression of hepatocellular carcinoma is discussed to provide reference for clinical treatment and drug development.

Insect neuropeptide receptors, including allatostatin receptor type C (AstR-C), a G protein-coupled receptor, are among the potential targets for designing next-generation pesticides that despite their importance in offering a new mode-of-action have been overlooked. Focusing on AstR-C of Thaumetopoea pityocampa, a common pest in Mediterranean countries, by employing resonance energy transfer-based methods, we showed Gαi/o coupling and β-arrestin recruitment of the receptor at sub-nanomolar and nanomolar ranges of the endogenous ligand, AST-C, respectively. Molecular docking and molecular dynamics simulation studies revealed the importance of extracellular loop 2 in AstRC/AST-C interaction, and a combination of in silico and in vitro approaches showed the substantial role of Q2716.55 in G protein-dependent activation of AstR-C possibly via contributing to the flexibility of the receptor's structure. The functional and structural insights obtained on T. pit AstR-C positively assist future efforts in developing environmentally friendly pest control agents that are needed urgently.

Identification of mutations in the gene encoding the inositol 1,4,5-trisphosphate receptor Type 1 (IP3R1) as causative for Spinocerebellar Ataxia 15, 29 and Gillespie Syndrome emphasize the importance of understanding how the IP3R impacts neuronal function and physiology. Here we discuss how cellular changes due to IP3 mediated Ca2+release affect systemic physiology in Drosophila and mouse. The relevance of these findings to recently identified human neurological conditions are also discussed.

Background Protein tyrosine phosphatase receptor type delta (PTPRD) is a tumor suppressor that is often inactivated in hepatocellular carcinoma (HCC). However, the mechanisms of how PTPRD inhibits HCC are not well understood. Programmed cell death ligand 1 (PD-L1), an immune checkpoint, plays a seminal role in the regulation of carcinogenesis of HCC. The sustained activation of STAT3 is closely related to PTPRD deletion and PD-L1 overexpression; however, whether there is a relationship between PTPRD and PD-L1 expression in HCC has not been investigated. This study aims to investigate the relationship between PTPRD and PD-L1 in HCC samples and illuminate potential new molecular mechanisms of PTPRD effects on PD-L1 in HepG2 cells. Methods We collected 16 pairs of tumorous tissues and adjacent normal tissues from HCC patients. The mRNA and protein expression levels of PTPRD and PD-L1 in the HCC tissues were detected by RT-PCR and Western blot analysis. Next, Spearman’s correlation analysis was performed to evaluate the relationship between PTPRD and PD-L1. Then, we transfected the overexpressed or knocked-down PTPRD genes into the HepG2 cell line, and the effects of PTPRD on PD-L1 in HCC cells were evaluated. The activity from the STAT3 and p-STAT3 in the HepG2 cells transfected with PTPRD gene overexpression and knockdown was determined by Western blotting tests. Results The expression of PTPRD was significantly down-regulated in the HCC tissues compared with the adjacent control tissues; however, PD-L1 was significantly higher in the HCC tissues. There was a negative correlation between PTPRD and PD-L1 expression in the HCC tissues. PTPRD over-expression significantly inhibited PD-L1 expression; meanwhile, PTPRD depletion promoted PD-L1 expression in the HepG2 cells. Furthermore, PTPRD over-expression significantly inhibited the expression of STAT3 and p-STAT3, while PTPRD depletion promoted these cytokines. Our studies revealed that PTPRD repressed PD-L1 expression in the HepG2 cells, which might occur via the STAT3 pathway. Conclusions The results from our study show that PTPRD and PD-L1 are negatively correlated in HCC tissues. PTPRD suppresses PD-L1 expression in HepG2 cells by down-regulating STAT3. These findings are expected to become a new target for the immunotherapy of HCC.

Transforming growth factor-β (TGFβ) has pleiotropic actions, including both anti- and pro-tumorigenic abilities. We have previously shown no tumor development in the thyroid-specific TGFβ receptor type II knockout (Tgfβr2 KO) mice, indicating the insufficiency of defective TGFβ signal itself for thyroid cancer initiation. In the current study, we evaluated whether defective TGFβ signal accelerates BRAFV600E-mediated thyroid carcinogenesis in our mouse model, in which intrathyroidal injection of adenovirus expressing Cre under thyroglobulin (TG) promoter (Ad-TgP-Cre) into thyroid lobes of conditional BrafV600E knock-in mice (BrafCA) induces thyroid cancers 12 months later. BrafCA/wt;Tgfbr2floxE2/floxE2 mice were generated by crossing Tgfbr2floxE2/floxE2 and BrafCA mice, and Ad-TgP-Cre was injected into the left lobes of 4–6-week-old mice. Mice were sacrificed at 6 and 12 months, and the thyroid tissues were subjected to HETgfbr2floxE2/floxE2 mice were all E-cadherin+/vimentin−, that is, epithelial type. In a mouse model, defective TGFβ signaling pathway accelerates BRAFV600E-induced thyroid cancer development, which is occasionally accompanied by reduced TG expression implying dedifferentiation. The former finding is consistent with anti-tumorigenic ability of TGFβ in early tumorigenic process, but the latter is contradictory to generally accepted concept for TGFβ-induction of dedifferentiation.

Pulmonary hypertension and hereditary hemorrhagic telangiectasia (HHT) have an association mediated by activin A receptor type II-like 1 (ACVRL1) gene pathogenic variants. A 30-year-old woman was previously admitted to a hospital due to lung hemorrhage, and was diagnosed with pulmonary hypertension, but stopped follow-up visits. At 48 years of age, she was admitted to our hospital and was diagnosed with HHT. Genetic testing revealed an ACVRL1 pathogenic variant. After the initiation of pulmonary vasodilator treatment, the patient's mean pulmonary artery pressure started to decrease from 43 mmHg, declining to 37 mmHg when she was 58 years of age. This is the first report describing the 28-year follow-up of an HHT and pulmonary hypertension patient with an ACVRL1 mutation.

The members of the protein tyrosine phosphatase (PTP) family are key regulators in multiple signal transduction pathways and therefore they play important roles in many cellular processes, including immune response. As a member of PTP family, protein tyrosine phosphatase receptor type O (PTPRO) belongs to the R3 receptor-like protein tyrosine phosphatases. The expression of PTPRO isoforms is tissue-specific and the truncated PTPRO (PTPROt) is mainly observed in hematopoietic cells, including B cells, T cells, macrophages and other immune cells. Therefore, PTPROt may play an important role in immune cells by affecting their growth, differentiation, activation and immune responses. In this review, we will focus on the regulatory roles and underlying molecular mechanisms of PTPRO/PTPROt in immune cells, including B cells, T cells, and macrophages.

Background: Hypertension (HTN) causes vascular injury identified by endothelial dysfunction, vascular stiffening, and remodeling, which contributes to kidney damage leading to chronic kidney disease (CKD). MicroRNAs (miRNAs) repress/degrade target mRNAs. Their role in vascular injury in HTN remains unclear. We aimed to identify differentially expressed (DE) miRNAs in gluteal subcutaneous arteries of patients with HTN associated or not with CKD to shed light on the pathophysiological molecular mechanisms. Methods: Normotensive subjects and patients with HTN associated or not with CKD grades 3-4 were studied (n=15-16). Small arteries were isolated from gluteal subcutaneous biopsies, RNA extracted and small and total RNA sequencing performed by Illumina HiSeq-2500. DE genes were identified with a P 1.3. Top 3 DE miRNAs ( P 2, mean read count number (MRCN) >3,000 in all groups and having predicted mRNA targets) were selected for validation by reverse transcription-quantitative PCR (RT-qPCR). The mRNA targets of the top selected miRNA were predicted by TargetScan with P 1.5 and MRCN>150 and the top 9 targets were validated by RT-qPCR using gain- and loss-of-function in human aortic endothelial cells (HAECs). Gene ontology enrichment analysis (GOEA) was done in Cytoscape. Results: DE miRNAs and mRNAs were identified uniquely associated with HTN (miRNAs: 10, mRNAs: 68), CKD (miRNAs: 68, mRNAs: 395), and in both groups (miRNAs: 2, mRNAs: 32). miR-338-3p presented the best correlation between RNA sequencing and RT-qPCR (R 2 =0.328, P PTPRS , FC: 0.80±0.08 vs 1.00±0.00) and glutathione peroxidase 3 ( GPX3 , FC: 0.88±0.04 vs 1.00±0.00) were down-regulated in HAECs transfected with miR-338-3p mimics ( P GPX3 with oxidative stress detoxification ( q PTPRS with the immune system, neuronal system and developmental process ( q Conclusion: Down-regulated miR-338-3p in gluteal subcutaneous small arteries of hypertensive patients with CKD targets PTPRS and GPX3 that may play a role in vascular injury in HTN.

Gynecologic cancers including cancers of the endometrium are a clinical problem (1-4). We mined published microarray data (5, 6) to discover genes associated with endometrial cancers by comparing transcriptomes of the normal endometrium and endometrial tumors from humans. We identified inositol 1,4,5-trisphosphate receptor type 3, encoded by ITPR3, as among the most differentially expressed genes, transcriptome-wide, in cancers of the endometrium. ITPR3 was expressed at significantly higher levels in endometrial tumor tissues as compared to the endometrium. Importantly, in human endometrial cancer, primary tumor expression of ITPR3 was correlated with overall survival in white patients with low mutational burden. ITPR3 may be a molecule of interest in understanding the etiology or progression of human endometrial cancer.

Apathy is a pervasive clinical phenomenon that deserves more attention at the translational and pre-clinical levels. To study apathy-like behavior in mice, we relied on an operational definition of apathy: the quantitative reduction of voluntary, goal-directed behaviors. We recently found that the chronic loss of function of a specific cell type (striatal dopamine receptor type 2-expressing medium spiny neurons, D2-MSN) in a restricted region (the ventrolateral striatum, VLS) was sufficient to induce apathy-like behavior in a food-seeking operant task. We further showed that VLS D2-MSN are activated at the preparatory period, and that optogenetic inhibition of VLS D2-MSN during that period resulted in transient decreases in instrumental motivation, strengthening the hypothesis that VLS D2-MSN mediate apathy-like behavior in mice. Mice bearing VLS D2-MSN dysfunction can thus be regarded as an apathy model for future translational studies.

Belonging to the group of cytokines, transforming growth factor-β is involved in numerous physiological processes with two of its main receptors/kinases – transforming growth factor-β receptor type 1 and 2. The inhibition of transforming growth factor-β receptor type 1 has numerous therapeutic applications, including application in glaucoma filtration surgery. This study presents QSAR modeling for a group of compounds that act as transforming growth factor-β receptor type 1 inhibitors based on field-based three dimensional modeling and the Monte Carlo method with descriptors based on the simplified molecular-input line-entry system notation and local invariants of molecular graphs. One random split of the initial data into the training and test sets was used to establish the 3D QSAR model, while for establishing conformation independent models three random splits into the training and test sets were used. The comparison of the obtained results for the molecular fragment influence on the studied activity obtained from both QSAR models revealed an excellent correlation. In order to assess the statistical quality of the developed models, different statistical approaches were applied and the results proved to be very good. The study defined molecular fragments responsible for the increase and/or decrease of the studied activity and then they were used for the computer-aided design of new compounds as potential transforming growth factor-β receptor type 1 inhibitors. The final evaluation of the established QSAR models and designed inhibitors was carried out using molecular docking studies, bringing to light an excellent correlation with the quantitative structure–activity relationship modeling results.

SummaryThe convergent evolution of the fly and mouse olfactory system led us to ask whether the anatomic connectivity and functional logic of olfactory circuits would evolve in artificial neural networks trained to perform olfactory tasks. Artificial networks trained to classify odor identity recapitulate the connectivity inherent in the olfactory system. Input units are driven by a single receptor type, and units driven by the same receptor converge to form a glomerulus. Glomeruli exhibit sparse, unstructured connectivity to a larger, expansion layer of Kenyon cells. When trained to both classify odor identity and to impart innate valence onto odors, the network develops independent pathways for identity and valence classification. Thus, the defining features of fly and mouse olfactory systems also evolved in artificial neural networks trained to perform olfactory tasks. This implies that convergent evolution reflects an underlying logic rather than shared developmental principles.

TNFα participates in a variety of physiological processes, but at supra-physiological concentrations it has been implicated in the pathology of inflammatory and autoimmune diseases. Therefore, much attention has been devoted to the development of strategies that overcome the effects of aberrant TNFα concentration. Promising strategies include drugs that destabilize the active (trimeric) form of TNFα and antagonists of TNFα receptor type I. Underpinning these strategies is the successful application of phage-display technology to identify anti-TNFα peptides and antibodies. Here, we review the development of inhibitors of the TNFα-TNF receptor system, with particular focus on the phage-display-assisted identification of molecules that interfere with this system by acting as inhibitors of TNFα or by sequestering TNFα away from its receptor.

The basolateral amygdala (BLA) is a critical brain region for cocaine-memory reconsolidation. Corticotropin-releasing factor receptor type 1 (CRFR1) is densely expressed in the BLA, and CRFR1 stimulation can activate intra-cellular signaling cascades that mediate memory reconsolidation. Hence, we tested the hypothesis that BLA CRFR1 stimulation is necessary and sufficient for cocaine-memory reconsolidation. Using an instrumental model of drug relapse, male and female Sprague-Dawley rats received cocaine self-administration training in a distinct environmental context over 10 days followed by extinction training in a different context over 7 days. Next, rats were re-exposed to the cocaine-paired context for 15 min to initiate cocaine-memory retrieval and destabilization. Immediately or 6 h after this session, the rats received bilateral vehicle, antalarmin (CRFR1 antagonist; 500 ng/hemisphere), or corticotropin-releasing factor (CRF; 0.2, 30 or 500 ng/hemisphere) infusions into the BLA. Resulting changes in drug context-induced cocaine seeking (index of context-cocaine memory strength) were assessed three days later. Female rats self-administered more cocaine infusions and exhibited more extinction responding than males. Intra-BLA antalarmin treatment immediately after memory retrieval (i.e., when cocaine memories were labile), but not 6 h later (i.e., after memory reconsolidation), attenuated drug context-induced cocaine seeking at test independent of sex, relative to vehicle. Conversely, intra-BLA CRF treatment increased this behavior selectively in females, in a U-shaped dose-dependent fashion. In control experiments, a high (behaviorally ineffective) dose of CRF treatment did not reduce BLA CRFR1 cell-surface expression in females. Thus, BLA CRFR1 signaling is necessary and sufficient, in a sex-dependent manner, for regulating cocaine-memory strength.

The term “privileged structure” refers to a single molecular substructure or scaffold that can serve as a starting point for high‐affinity ligands for more than one receptor type. In this report, a hitherto overlooked group of privileged substructures is addressed, namely aromatic oligoamides, for which there are natural models in the form of cystobactamids, albicidin, distamycin A, netropsin, and others. The aromatic and heteroaromatic core, together with a flexible selection of substituents, form conformationally well‐defined scaffolds capable of specifically binding to conformationally well‐defined regions of biomacromolecules such as helices in proteins or DNA often by acting as helices mimics themselves. As such, these aromatic oligoamides have already been employed to inhibit protein–protein and nucleic acid–protein interactions. This article is the first to bring together the scattered knowledge about aromatic oligoamides in connection with biomedical applications., Privileged! Aromatic oligoamides based on pyrroles, pyridines, and p‐aminobenzoic acids are presented as privileged structures that efficiently target nucleic acids and proteins as well as complexes derived therefrom. Their design can be related to natural products such distamycin A and the cystobactamids.

Heterotopic ossification (HO) is a disorder characterised by the formation of ectopic bone in soft tissue. Acquired HO typically occurs in response to trauma and is relatively common, yet its aetiology remains poorly understood. Genetic forms, by contrast, are very rare, but provide insights into the mechanisms of HO pathobiology. Fibrodysplasia ossificans progressiva (FOP) is the most debilitating form of HO. All patients reported to date carry heterozygous gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1). These mutations cause dysregulated bone morphogenetic protein (BMP) signalling, leading to HO at extraskeletal sites including, but not limited to, muscles, ligaments, tendons and fascia. Ever since the identification of the causative gene, developing a cure for FOP has been a focus of investigation, and studies have decoded the pathophysiology at the molecular and cellular levels, and explored novel management strategies. Based on the established role of BMP signalling throughout HO in FOP, therapeutic modalities that target multiple levels of the signalling cascade have been designed, and some drugs have entered clinical trials, holding out hope of a cure. A potential role of other signalling pathways that could influence the dysregulated BMP signalling and present alternative therapeutic targets remains a matter of debate. Here, we review the recent FOP literature, including pathophysiology, clinical aspects, animal models and current management strategies. We also consider how this research can inform our understanding of other types of HO and highlight some of the remaining knowledge gaps., Summary: Fibrodysplasia ossificans progressiva is a rare disease characterised by progressive heterotopic bone formation. Here, we present a comprehensive summary of the recent literature on this debilitating condition and discuss approaches to solving this clinical puzzle.

To characterize the phenotypic abnormalities of peripheral B cells in patients with Graves' orbitopathy (GO) and explore the role of chemokine CXC ligand 13 and its receptor type 5 (CXCL13/CXCR5) in relation to B-cell homeostasis using specific neutralizing antibodies.Adults with active GO (n = 22), inactive GO (n = 28), and healthy control subjects (n = 28) were included in the study. Peripheral B cells and B-cell subsets were quantified and analyzed for CXCR5 expression by flow cytometry. The serum CXCL13 concentration was measured by enzyme-linked immunosorbent assays. For chemotactic experiments, Transwell plates were used, and migrating B cells were further analyzed by flow cytometry.Compared to healthy subjects, patients with active GO had a significantly higher number of CD19Our data suggest that aberrant CXCL13/CXCR5 expression may contribute to the deficits in B-lymphocyte homeostasis observed in active GO.

Background Angiotensin II (Ang II ) can cause hypertension and tissue impairment via AGTR 1 (Ang II receptor type 1), particularly in renal proximal tubule cells, and can cause DNA damage in renal cells via nicotinamide adenine dinucleotide phosphate oxidase. BubR1 (budding uninhibited by benzimidazole‐related 1) is a multifaceted kinase that functions as a mitotic checkpoint. BubR1 expression can be induced by Ang II in smooth muscle cells in vitro, but the relationship between systemic BubR1 expression and the Ang II response is unclear. Methods and Results Twenty 24‐week‐old male BubR1 low‐expression mice (BubR1 L/L mice) and age‐matched BubR1 +/+ mice were used in this study. We investigated how Ang II stimulation affects BubR1 L/L mice. The elevated systolic blood pressure caused by Ang II stimulation in BubR1 +/+ mice was significantly attenuated in BubR1 L/L mice. Additionally, an attenuated level of Ang II –induced perivascular fibrosis was observed in the kidneys of BubR1 L/L mice. Immunohistochemistry revealed that the overexpression of AGTR 1 induced by Ang II stimulation was repressed in BubR1 L/L mice. We evaluated AGTR 1 and Nox‐4 (nicotinamide adenine dinucleotide phosphate oxidase‐4) levels to determine the role of BubR1 in the Ang II response. Results from in vitro assays of renal proximal tubule cells suggest that treatment with small interfering RNA targeting BubR1 suppressed Ang II ‐induced overexpression of AGTR 1. Similarly, the upregulation in Nox4 and Jun N‐terminal kinase induced by Ang II administration was repressed by treatment with small interfering RNA targeting BubR1. Conclusions Ang II –induced hypertension is caused by AGTR 1 overexpression in the kidneys via the upregulation of BubR1 and Nox4.

Objective— Diabetic macular edema is a major cause of visual impairment. It is caused by blood-retinal barrier breakdown that leads to vascular hyperpermeability. Current therapeutic approaches consist of retinal photocoagulation or targeting VEGF (vascular endothelial growth factor) to limit vascular leakage. However, long-term intravitreal use of anti-VEGFs is associated with potential safety issues, and the identification of alternative regulators of vascular permeability may provide safer therapeutic options. The vascular specific BMP (bone morphogenetic protein) receptor ALK1 (activin-like kinase receptor type I) and its circulating ligand BMP9 have been shown to be potent vascular quiescence factors, but their role in the context of microvascular permeability associated with hyperglycemia has not been evaluated. Approach and Results— We investigated Alk1 signaling in hyperglycemic endothelial cells and assessed whether BMP9/Alk1 signaling could modulate vascular permeability. We show that high glucose concentrations impair Alk1 signaling, both in cultured endothelial cells and in a streptozotocin model of mouse diabetes mellitus. We observed that Alk1 signaling participates in the maintenance of vascular barrier function, as Alk1 haploinsufficiency worsens the vascular leakage observed in diabetic mice. Conversely, sustained delivery of BMP9 by adenoviral vectors significantly decreased the loss of retinal barrier function in diabetic mice. Mechanistically, we demonstrate that Alk1 signaling prevents VEGF-induced phosphorylation of VE-cadherin and induces the expression of occludin, thus strengthening vascular barrier functions. Conclusions— From these data, we suggest that by preventing retinal vascular permeability, BMP9 could serve as a novel therapeutic agent for diabetic macular edema.

TNF-α is a crucial cytokine in the process of inflammatory diseases. The adverse effect of TNF-α is mostly mediated by interaction of TNF-α with TNF-α receptor type I (TNFR1); therefore, discovery of molecules which can bind to TNFR1 preventing TNF-α-receptor complex formation would be of great interest. In the current study, using GRID/GOLPE program, a 3D-QSAR study was conducted on a series of synthetic TNFR1 binders, which resulted in a 3D-QSAR model with appropriate power of predictivity in internal (r2 = 0.94 and q2LOO = 0.74) and external (r2 = 0.66 and SDEP = 0.42) validations. The structural features of TNFR1 inhibitors essential for exerting activity were explored by analyzing the contour maps of the 3D-QSAR model showing that steric interactions and hydrogen bonds are responsible for exerting TNFR1 inhibitory activity. To propose potential chemical entities for TNFR1 inhibition, PubChem database was searched and the selected compounds were virtually tested for anti-TNFR1 activity using the generated model, resulting in two potential anti-TNFR1 compounds. Finally, the possible interactions of the compounds with TNFR1 were investigated using docking studies. The findings in the current work can pave the way for designing more potent anti-TNFR1 inhibitors.

Members of the transient receptor potential (TRP) family, such as the vanilloid receptor type 1 (TRPV1), have been shown to play a significant role in nociception. Activation of TRPV1 not only causes pain, but can also lead to inflammation in the surrounding tissues through the induced influx of primarily Ca2+ ions into the cytosol. Therefore agonistic properties of a compound towards TRPV1 might indicate harmful environmental stimuli, which can be screened for using various low and high throughput in vitro methods. Prediction of such properties for novel entities using existing data is of importance, however the generation of in silico models are usually difficult due to the high class imbalance ratio present within these datasets. This imbalance can be quite significant, such as in the case of PubChem BioAssay AID 540275, with the inactive:active ratio of 484:1. In this study, we propose a first-tier high throughput in silico screening approach using the Mondrian Conformal Prediction framework, to identify potential agonists of TRPV1 from 2D molecular structures using RDKit descriptors in the PubChem BioAssay AID 540275 dataset.

Background Improvement in genetic characterization of Colon Cancer (CC) patients is required to propose new potential targets, since surgical resection coupled to chemotherapy, presents several limits such as cancer recurrence and drug resistance. Targeted therapies have more efficacy and less toxicity than standard treatments. One of the most relevant cancer-specific actionable targets are receptor tyrosine kinases (RTKs) whose role in CC need to be better investigated. Methods We have analysed 37 CC patients using the Ion AmpliSeq™ Comprehensive Cancer Panel (CCP). We have confirmed the somatic nature of RET variants through Sanger sequencing and assessed RET activation status and protein expression by immunofluorescence and western-blot analyses. We have used RET mutant expression vectors to evaluate the effect of selected mutations in HEK293 cells by performing proliferation, migration and clonogenic assays. Results Among the 409 cancer-related genes included in the CCP we have focused on the RTKs. Overall, we have observed 101 different potentially damaging variants distributed across 31 RTK genes in 28 patients. The most frequently mutated RTKs were FLT4, ROS1, EPH7, ERBB2, EGFR, RET, FGFR3 and FGFR4. In particular, we have identified 4 different somatic variants in 10% of CC patients in RET proto-oncogene. Among them, we have demonstrated that the G533C variant was able to activate RET by promoting dimer formation and enhancing Y1062 phosphorylation. Moreover, we have demonstrated that RET G533C variant was able to stimulate anchorage-dependent proliferation, migration and clonogenic cell survival. Notably, the effects induced by the RET G533C variant were abolished by vandetanib. Conclusions The discovery of pathogenic variants across RTK genes in 75% of the CC patients under analysis, suggests a previously underestimated role for RTKs in CC development. The identification of a gain-of-function RET mutation in CC highlights the potential use of RET in targeted therapy. Electronic supplementary material The online version of this article (10.1186/s13046-018-0746-y) contains supplementary material, which is available to authorized users.

The severity of cardiac dysfunction predicts mortality in sepsis. Activation of transient receptor potential vanilloid receptor type (TRPV)-1, a predominantly neuronal nonselective cation channel, has been shown to improve outcome in sepsis and endotoxemia. However, the role of TRPV1 and the identity of its endogenous ligands in the cardiac dysfunction caused by sepsis and endotoxemia are unknown. Using TRPV1

Receptor-specific peptides labeled with positron emitters play an important role in the clinical imaging of several malignancies by positron emission tomography (PET). Radiolabeled heterobivalent bispecific peptidic ligands (HBPLs) can target more than one receptor type and by this - besides exhibiting other advantages - increase tumor imaging sensitivity. In the present study, we show the initial in vivo evaluation of the most potent heterobivalent gastrin-releasing peptide receptor (GRPR)- and vasoactive intestinal peptide receptor subtype 1 (VPAC1R)-bispecific radiotracer and determined its tumor visualization potential via PET/CT imaging. For this purpose, the most potent described HBPL was synthesized together with its partly scrambled heterobivalent monospecific homologs and its monovalent counterparts. The agents were efficiently labeled with 68Ga3+ and evaluated in an initial PET/CT tumor imaging study in a human prostate carcinoma (PCa) xenograft rat tumor model established for this purpose. None of the three 68Ga-HBPLs enabled a clear tumor visualization and a considerably higher involvement in receptor-mediated uptake was found for the GRPR-binding part of the molecule than for the VPAC1R-binding one. Of the monovalent radiotracers, only [68Ga]Ga-NODA-GA-PESIN could efficiently delineate the tumor, confirming the results. Thus, this work sets the direction for future developments in the field of GRPR- and VPAC1R-bispecific radioligands, which should be based on other VPAC1R-specific peptides than PACAP-27.

Neurodegenerative and cerebrovascular diseases are frequent in elderly populations and comprise primarily of dementia (mainly Alzheimer's disease) Parkinson's disease and stroke. These neurological disorders (NDs) occur as a result of neurodegenerative processes and represent one of the most frequent causes of death and disability worldwide with a significant clinical and socio-economic impact. Although NDs have been characterized for many years, the exact molecular mechanisms that govern these pathologies or why they target specific individuals and specific neuronal populations remain unclear. As research progresses, many similarities appear which relate these diseases to one another on a subcellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate the conditions of many diseases simultaneously. G-protein coupled receptors (GPCRs) are the most abundant receptor type in the central nervous system and are linked to complex downstream pathways, manipulation of which may have therapeutic application in many NDs. This review will highlight the potential use of neurotransmitter GPCRs as emerging therapeutic targets for neurodegenerative and cerebrovascular diseases.

Different types of lightning protection system (LPS) are being used for wind turbine blades (WTBs). However, still severe damages due to lightning strikes still happen frequently, which costs huge losses. In this paper, a review on experimental study of WTB lightning protection is given. Experiments were performed to study the lightning attachment characteristics of glass fiber reinforced polymer (GFRP) composite wind turbine blade. Experiments using three specimens of WTB the effect of wind turbine blade orientation, lateral distances (LDs) between the wind turbine blade and the lightning downward leader, polarity of lightning strike, wind turbine blade rotation speed, receptor type and marine environment on lightning interception failure of LPS in different situation were studied. It was observed that discharge attachment paths under positive and negative lightning strikes were quite different, and the positive discharges are much more dangerous to wind turbine blade than the negative ones. The LD between downward leader and WTB is a key factor which influences the interception efficiency. The experiment results can be useful to improve the optimal design of LPS of WTBs.

The Corticotropin-Releasing Factor (CRF) is a neuropeptide released by the hypothalamus in response to stress. CRF activates the CRF1 and CRF2 receptors, which are members of the G protein-coupled receptor (GPCR) superfamily. Although it has been shown that the CRF1 receptor activates ERK 1/2 cascade in different cell models [1] however, to date is not well understood the roles of upstream pathways associated with this effects. β-arrestin2 is an adapter protein that participates in the regulation of GPCRs and has important functions in cell signaling by mediating activation of multiple transductional pathways, including Src and MAPK [2]. In the present work, we investigated the role of β-arrestin2 in the activation of MAPK by induction of 100 nM CRF. We used mouse embryonic fibroblast cells that lack β-arrestin2 (MEF KO-β-arrestin2), transfected with the CRF1 receptor that lack β-arrestin2 (MEF KO-β-arrestin2) as model. Our data revealed that β-arrestin2 is involved in the activation of ERK 1/2 since we detected lower (P

INTRODUCTION AND OBJECTIVES:Psychological stress exacerbates bladder dysfunction such as overactive bladder (OAB) and bladder pain syndrome/interstitial cystitis (BPS/IC). We previously reported that bombesin (BB), a stress-related neuropeptide, centrally induces facilitation of the rat micturition reflex. Brain BB is reported to activate hypothalamo-pituitary-adrenal axis and sympathetic nerves, as representative responses to stressful conditions, via brain corticotropin-releasing factor (CRF), another stress-related neuropeptide. Therefore, we examined whether brain CRF is involved in the BB-induced frequent urination in rats.METHODS:(1) In urethane anesthetized (0.8 g/kg, ip) male Sprague-Dawley (SD) rats (300-400 g), a catheter was inserted into the bladder to perform cystometry (CMG, 12 ml/h saline infusion). Astressin (a non-selective CRF receptor antagonist, 1 or 3 nmol/rat) was intracerebroventricularly (icv) pretreated 60 min before BB administration (0.03 nmol/rat, icv). CMG was started 60 min b...

The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies amp;lt; 60 Hz) and vibratory hum (frequencies amp;gt; 60 Hz), subserved by two distinct receptor types (Meissners and Pacinian corpuscle, respectively), which may engage different neural processing pathways or channels and fulfil quite different biological roles. In psychological and physiological literature, those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency, thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types. Funding Agencies|National Health and Medical Research Council [APP1028284, DP170100064]

Musculoskeletal disorders represent an elevated socioeconomic burden for developed aging societies. Osteoporosis (OP) has been treated with antiresorptive therapies or with teriparatide that was until recently the only anabolic therapy. However, approval of osteoporosis treatment in postmenopausal women with abaloparatide, which is an analog of parathyroid hormone-related peptide (PTHrP), has created a new alternative for OP management. The success of this new treatment is related to differential mechanisms of activation of PTH receptor type 1 (PTH1R) by abaloparatide and PTH. Here, we address the distinguishing mechanisms of PTH1R activation; the effects of PTH1R stimulation in osteoblast, osteocytes, and chondrocytes; the differences between PTH and abaloparatide actions on PTH1R; potential safety concerns; and future perspectives about abaloparatide use in other musculoskeletal disorders.

Olfactory receptor usage is highly heterogeneous, with some receptor types being orders of magnitude more abundant than others. We propose an explanation for this striking fact: the receptor distribution is tuned to maximally represent information about the olfactory environment in a regime of efficient coding that is sensitive to the global context of correlated sensor responses. This model predicts that in mammals, where olfactory sensory neurons are replaced regularly, receptor abundances should continuously adapt to odor statistics. Experimentally, increased exposure to odorants leads variously, but reproducibly, to increased, decreased, or unchanged abundances of different activated receptors. We demonstrate that this diversity of effects is required for efficient coding when sensors are broadly correlated, and provide an algorithm for predicting which olfactory receptors should increase or decrease in abundance following specific environmental changes. Finally, we give simple dynamical rules for neural birth and death processes that might underlie this adaptation., eLife digest A mouse’s nose contains over 10 million receptor neurons divided into about 1,000 different types, which detect airborne chemicals – called odorants – that make up smells. Each odorant activates many different receptor types. And each receptor type responds to many different odorants. To identify a smell, the brain must therefore consider the overall pattern of activation across all receptor types. Individual receptor neurons in the mammalian nose live for about 30 days, before new cells replace them. The entire population of odorant receptor neurons turns over every few weeks, even in adults. Studies have shown that some types of these receptor neurons are used more often than others, depending on the species, and are therefore much more abundant. Moreover, the usage patterns of different receptor types can also change when individual animals are exposed to different smells. Teşileanu et al. set out to develop a computer model that can explain these observations. The results revealed that the nose adjusts its odorant receptor neurons to provide the brain with as much information as possible about typical smells in the environment. Because each smell consists of multiple odorants, each odorant is more likely to occur alongside certain others. For example, the odorants that make up the scent of a flower are more likely to occur together than alongside the odorants in diesel. The nose takes advantage of these relationships by adjusting the abundance of the receptor types in line with them. Teşileanu et al. show that exposure to odorants leads to reproducible increases or decreases in different receptor types, depending on what would provide the brain with most information. The number of odorant receptor neurons in the human nose decreases with time. The current findings could help scientists understand how these changes affect our sense of smell as we age. This will require collaboration between experimental and theoretical scientists to measure the odors typical of our environments, and work out how our odorant receptor neurons detect them.