25 de Abril Sempre! Portuguese Science and the 50th anniversary of the Carnation Revolution

In 2024, Portugal celebrates the 50th anniversary of the Carnation Revolution, which brought down a long dictatorship and re-instated elemental civil liberties and democracy in the country. For Portuguese science, this revolution meant a democratisation of access to the scientific career and an increased investment in scientific research, which culminated in an unprecedented rise in scientific output. Communications Biology joins this anniversary and celebrations of freedom and democracy as basic pillars of scientific endeavour

Spatial Distribution of the Cannabinoid Type 1 and Capsaicin Receptors May Contribute to the Complexity of Their Crosstalk

Angelika Varga has been supported by a European Union Marie Curie Intra-European Fellowship (254661), a Hungarian Social Renewal Operation Program (TÁMOP 4.1.2.E-13/1/KONV-2013-0010) and the Hungarian Brain Research program (KTIA_NAP_13-2-2014-0005) of the Hungarian Government. Agnes Jenes has been supported by a BJA/RCoA Project Grant. This work has also been supported, in part, by the BIOSS-2 Grant, Project A6.

Phosphorylated Histone 3 at Serine 10 Identifies Activated Spinal Neurons and Contributes to the Development of Tissue Injury-Associated Pain

Transcriptional changes in superficial spinal dorsal horn neurons (SSDHN) are essential in the development and maintenance of prolonged pain. Epigenetic mechanisms including post-translational mo difications in histones are pivotal in regulating transcription. Here, we report th at phosphorylation of serine 10 (S10) in histone 3 (H3) specifically occurs in a group of rat SSDHN following the activation of nociceptive primary sensory neurons by burn injury, capsaicin application or sustained electrical activation of nociceptive primary sensory nerve fibres. In contrast, brief thermal or mechanical nociceptive stimuli, which fail to induce tissue injury or inflammation, do not produce the same effect. Blocking N-methyl-D-aspartate receptors or activation of extracellular signa l-regulated kinases 1 and 2, or blocking or deleting the mitogen- and stress-activated kinases 1 and 2 (MSK1/2), which phosphorylate S10 in H3, inhibit up-regulation in phosphorylated S10 in H3 ( p - S10H3) as well as fos transcription, a down-stream effect of p -S10H3. Deleting MSK1/2 also inhibits the development of carrageenan-induced inflammatory heat hyperalgesia in mice. We propose that p -S10H3 is a novel marker for nociceptive processing in SSDHN with high relevance to transcriptional changes and the development of prolonged pain

Evidence That a TRPA1-Mediated Murine Model of Temporomandibular Joint Pain Involves NLRP3 Inflammasome Activation

From MDPI via Jisc Publications RouterHistory: accepted 2021-10-14, pub-electronic 2021-10-23Publication status: PublishedFunder: Versus Arthritis; Grant(s): 21541This study investigates the role of transient receptor potential ankyrin 1 (TRPA1) in murine temporomandibular joint (TMJ) inflammatory hyperalgesia and the influence of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Two distinct murine models of TMJ pain and inflammation (zymosan and CFA) were established. Spontaneous pain-like behaviours were observed as unilateral front paw cheek wipes. Ipsilateral cheek blood flow was used as a measure of ongoing inflammation, which, to our knowledge, is a novel approach to assessing real-time inflammation in the TMJ. Joint tissue and trigeminal ganglia were collected for ex vivo investigation. Both zymosan and CFA induced a time-dependent increase in hyperalgesia and inflammation biomarkers. Zymosan induced a significant effect after 4 h, correlating with a significantly increased IL-1β protein expression. CFA (50 µg) induced a more sustained response. The TRPA1 receptor antagonist A967079 significantly inhibited hyper-nociception. The NLRP3 inhibitor MCC950 similarly inhibited hyper-nociception, also attenuating inflammatory markers. In the trigeminal ganglia, CFA-induced CGRP expression showed trends of inhibition by A967079, whilst lba1 immunofluorescence was significantly inhibited by A967079 and MCC950, where the effect of TRPA1 inhibition lasted up to 14 days. Our results show that stimulation of TRPA1 is key to the TMJ pain. However, the inflammasome inhibitor exhibited similar properties in attenuating these pain-like behaviours, in addition to some inflammatory markers. This indicates that in addition to the therapeutic targeting of TRPA1, NLRP3 inhibition may provide a novel therapeutic strategy for TMJ inflammation and pain

Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazili an centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome83289298CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DO RIO GRANDE DO SUL - FAPERGSSem informaçãoSem informação2006/60402-1; 2010/51547-1; 2013/01476-9; 2014/06570-6; 2009/50575-4; 2010/51546-5; 2012/21942-116/2551-0000482-

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Role of the cannabinoid system in nociceptive processing in primary sensory neurons

The endogenous ligand N-arachydonoylethanolamine (anandamide) is an important modulator of nociceptive processing in primary sensory neurons (PSN), because it activates both the excitatory transient receptor potential vanilloid type 1 ion channel (TRPV1) and the inhibitory cannabinoid type-1 (CB1) receptor, which are co-expressed in PSN and plays a pivotal role in the development and maintenance of pain associated with peripheral pathologies. However, the mechanisms involved in the anandamide-mediated modulation of nociceptive processing in PSN are not well understood. Here, we studied some important aspects of anandamide-mediated signaling in PSN. We found that multiple anandamide-synthesising pathways are present in PSN. The only Ca2+-sensitive anandamide-synthesising enzyme, Nacylphosphatidylethanolamine phospholipase D (NAPE-PLD), exhibits a high degree of co-expression with TRPV1, the CB1 receptor and the main anandamide-hydrolysing enzyme, fatty acid amid hydrolase. Spinal nerve injury, but not inflammation significantly alters this expression pattern. Although, the excitatory effect of anandamide is mediated by TRPV1 in PSN, not all TRPV1- expressing cells respond to anandamide. Blocking or deleting the CB1 receptor significantly reduces anandamide responsiveness of TRPV1, and PSN either express TRPV1 and the CB1 receptor in segregation or in close association. Cultured spinal microglia, in addition to PSN, also synthesise anandamide and that synthesis may depend on the activation state of spinal microglia and involve the activity of phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 (Inpp5). 3 Our findings support the view that anandamide-mediated signalling may occur through autocrine mechanisms in PSN, and indicate that nerve injury may induce deregulation of that signalling which may contribute to the development of neuropathic pain. However, paracrine mechanisms, for example through anandamide synthesis in spinal microglia may also contribute to anandamide-mediated signalling, which is shaped, among others, by a complex crosstalk between the CB1 receptor and TRPV1. Finally, our findings suggest that NAPE-PLD and Inpp5 might be targets for future analgesics.Open Acces

A novel interaction between CX3CR1 and CCR2 signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain

Abstract Background A dose-limiting side effect of chemotherapeutic agents such as vincristine (VCR) is neuropathic pain, which is poorly managed at present. Chemokine-mediated immune cell/neuron communication in preclinical VCR-induced pain forms an intriguing basis for the development of analgesics. In a murine VCR model, CX3CR1 receptor-mediated signalling in monocytes/macrophages in the sciatic nerve orchestrates the development of mechanical hypersensitivity (allodynia). CX3CR1-deficient mice however still develop allodynia, albeit delayed; thus, additional underlying mechanisms emerge as VCR accumulates. Whilst both patrolling and inflammatory monocytes express CX3CR1, only inflammatory monocytes express CCR2 receptors. We therefore assessed the role of CCR2 in monocytes in later stages of VCR-induced allodynia. Methods Mechanically evoked hypersensitivity was assessed in VCR-treated CCR2- or CX3CR1-deficient mice. In CX3CR1-deficient mice, the CCR2 antagonist, RS-102895, was also administered. Immunohistochemistry and Western blot analysis were employed to determine monocyte/macrophage infiltration into the sciatic nerve as well as neuronal activation in lumbar DRG, whilst flow cytometry was used to characterise monocytes in CX3CR1-deficient mice. In addition, THP-1 cells were used to assess CX3CR1-CCR2 receptor interactions in vitro, with Western blot analysis and ELISA being used to assess expression of CCR2 and proinflammatory cytokines. Results We show that CCR2 signalling plays a mechanistic role in allodynia that develops in CX3CR1-deficient mice with increasing VCR exposure. Indeed, the CCR2 antagonist, RS-102895, proves ineffective in mice possessing functional CX3CR1 receptors but reduces VCR-induced allodynia in CX3CR1-deficient mice, in which CCR2 + monocytes are elevated by VCR. We suggest that a novel interaction between CX3CR1 and CCR2 receptors in monocytes accounts for the therapeutic effect of RS-102895 in CX3CR1-deficient mice. Indeed, we observe that CCR2, along with its ligand, CCL2, is elevated in the sciatic nerve in CX3CR1-deficient mice, whilst in THP-1 cells (human monocytes), downregulating CX3CR1 upregulates CCR2 expression via p38 MAP kinase signalling. We also show that the CX3CR1-CCR2 interaction in vitro regulates the release of pronociceptive cytokines TNF-α and IL1β. Conclusions Our data suggests that CCL2/CCR2 signalling plays a crucial role in VCR-induced allodynia in CX3CR1-deficient mice, which arises as a result of an interaction between CX3CR1 and CCR2 in monocytes

TRANSIENT RECEPTOR POTENTIAL ION CHANNELS IN PRIMARY SENSORY NEURONS AS TARGETS FOR NOVEL ANALGESICS

The last decade has witnessed an explosion in novel findings relating to the molecules involved in mediating the sensation of pain in human beings. Transient receptor potential ion channels emerged as the greatest group of molecules involved in the transduction of various physical stimuli into neuronal signals in primary sensory neurons as well as in the development of pain. Here, we review the role of transient receptor potential ion channels in primary sensory neurons in the development of pain associated with peripheral pathologies and possible strategies to translate pre-clinical data into the development of effective new analgesics. Based on available evidence, we argue that nociception-related TRP channels on primary sensory neurons provide highly valuable targets for the development of novel analgesics and that, in order to reduce possible undesirable side-effects, novel analgesics should prevent the translocation from the cytoplasm to the cell membrane and the sensitisation of the channels rather than blocking the channel pore or binding sites for exogenous or endogenous activators