Sarcoma anaplásico do rim DICER1 associado a nefroma cístico em criança do sexo masculino: relato de caso. Trabalho de Conclusão de Curso / Anaplastic sarcoma of the kidney DICER1 associated with cystic nephroma in a male child: case report

O Sarcoma Anaplásico Renal DICER1 é um tumor raro, com menos de 30 casos relatados desde 2007, que ocorre predominantemente no sexo feminino. É caracterizado macroscopicamente por uma grande massa renal heterogênea com áreas sólidas e císticas e histologicamente, pela presença de cistos, na maioria dos casos, e áreas sólidas compostas por células fusiformes indiferenciadas com marcada alteração anaplásica e áreas proeminentes de benignidade ou malignidade de diferenciação condróide ou cartilaginosa. Nosso caso ocorreu em um paciente do sexo masculino de 08 anos de idade que apresentava infecção do trato urinário (ITU) de repetição há dois anos, associado à dor lombar, com Tomografia Computadorizada (TC) evidenciando grande massa renal à direita. Foi operado de urgência, devido piora do quadro clínico, e suspeita de rotura intratumoral. Após nefrectomia à direita, o exame histopatológico mostrou Sarcoma anaplásico renal associado à nefroma cístico residual.

DICER1 Renal Anaplastic Sarcoma is a rare tumor, with less than 30 cases reported since 2007, which occurs predominantly in females. It is characterized macroscopically by a large heterogeneous renal mass with solid and cystic areas and histologically, by the presence of cysts, in most cases, and solid areas composed of undifferentiated spindle cells with marked anaplastic alteration and prominent areas of benignity or malignancy of chondroid differentiation or cartilaginous. Our case occurred in an 8- year-old male patient who had recurrent UTI for two years, associated with low back pain, with CT showing a big renal mass on the right. He underwent urgent surgery due to worsening of the clinical condition and suspicion of intra-tumoral rupture. Histopathological examination showed renal anaplastic sarcoma associated with residual cystic nephroma.

The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16176. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

A Community-Based Pre-Exposure Prophylaxis Telehealth Program Focused on Latinx Sexual Minority Men.

Latinx sexual minority men (LSMM) face multilevel barriers to accessing HIV pre-exposure prophylaxis (PrEP). To address these barriers, we designed and implemented community-based organization (CBO)-PrEP, a collaborative community-based telehealth PrEP program for LSMM. We designed this PrEP delivery program through a collaborative process involving staff from local CBOs and a primary care-based HIV prevention program. Staff met weekly over a 3-month period to establish protocols for referrals, obtaining insurance coverage, and navigation to appointments and laboratory testing. To assess feasibility, we extracted electronic medical record data including demographics and clinical outcomes of PrEP care. Between December 2020 and May 2023, 102 individuals were referred to CBO-PrEP of which 85 had Hispanic/Latino as their ethnicity in their medical records; out of 102 individuals, 72 (70.6%) were scheduled for an initial appointment. Out of 72 individuals scheduled for an appointment, 58 (80.6%) were seen by a health care provider a median of 7.5 days after referral [interquartile range (IQR), 2-19]; 48 (82.6%) of initial appointments were through telemedicine, 10 (17.2%) were seen in person. Of the 48 patients who had a telehealth appointment, 36 (75%) underwent initial laboratory testing and 42 (87.5) were prescribed PrEP; all 10 patients who were seen in person underwent laboratory testing and were prescribed PrEP. PrEP prescriptions were received in a median of 17.5 days (IQR 4.5-33.5) after referral. CBO-PrEP successfully engaged LSMM, a population that is often hard to reach. Expanding collaborative approaches with CBOs could have a significant impact on improving PrEP uptake for LSMM and other priority populations.

Are committee experiences of minoritized family medicine faculty part of the minority tax? a qualitative study.

BACKGROUND AND OBJECTIVES: Because much of the work in academic medicine is done by committee, early career URiM faculty, are often asked to serve on multiple committees, including diversity work that may not be recognized as important. They may also be asked to serve on committees to satisfy a diversity "check box," and may be asked more often than their non-URiM peers to serve in this capacity. We sought to describe the committee experiences of early career URiM faculty, hypothesizing that they may see committee service as a minority tax. METHODS: Participants in the Leadership through Scholarship Fellowship (LTSF) were asked to share their experiences with committee service in their careers after participating in a faculty development discussion. Their responses were analyzed and reported using qualitative, open, axial, and abductive reasoning methods. RESULTS: Four themes, with eight sub-themes (in parenthesis), emerged from the content analysis of the LTSF fellows responses to the prompt: Time commitment (Timing of committee work and lack of protected time for research and scholarship), URiM Committee service (Expectation that URiM person will serve on committees and consequences for not serving), Mentoring issues (no mentoring regarding committee service, faculty involvement is lacking and the conflicting nature of committee work) and Voice (Lack of voice or acknowledgement). CONCLUSIONS: Early career URiM faculty reported an expectation of serving on committees and consequences for not serving related to their identity, but other areas of committee service they shared were not connected to their URiM identity. Because most of the experiences were not connected to the LTSF fellows' URiM identity, this group has identified areas of committee service that may affect all early career faculty. More research is necessary to determine how committee service affects URiM and non-URiM faculty in academic family medicine.

Expansion of marine pollution along the coast: Negative effects on kelps and contamination transference to benthic herbivores?

Heavy metals and polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants that frequently co-occur in coastal environments. These contaminants can have negative impacts on the health and stability of marine and coastal ecosystems, affecting both the organisms themselves and the humans who consume them. A coastal industrial park in central Chile, housing a coal thermal power plant and other industrial activities, contributes to such pollution of coastal waters; however, neither the spatial alongshore distribution of heavy metals and PAHs, nor an assessment of their ecological effects on the biota have been systematically documented to date. In this paper, we present evidence regarding the direct negative effect of contamination by heavy metals and PAHs on the early life stages of kelps-being extremely harmful to their population persistence near highly polluted sites-as well as the indirect effects of their transference through the food web to higher trophic levels, leading to negative consequences for the feeding intake, growth, fertility, and larval development of marine herbivores that consume the contaminated seaweed. Likewise, the dispersion of contaminants by ocean currents can exacerbate the effects of pollution, having an adverse influence on marine ecosystem health even at sites far from the pollution source. Therefore, it is necessary to investigate the distribution patterns and extent of pollution along the coast to understand the impact of heavy metals and PAHs pollution on seaweed populations and the food web. It is considered critical for the development of effective environmental policies and regulations to protect these ecosystems and the people who depend on them.

Antimicrobial Resistance and Extended-Spectrum Beta-Lactamase Genes in Enterobacterales, Pseudomonas and Acinetobacter Isolates from the Uterus of Healthy Mares.

Antibiotic-resistant bacteria are a growing concern for human and animal health. The objective of this study was to determine the antimicrobial resistance and extended-spectrum beta-lactamase genes in Enterobacterales, Pseudomonas spp. and Acinetobacter spp. isolates from the uterus of healthy mares. For this purpose, 21 mares were swabbed for samples, which were later seeded on blood agar and MacConkey agar. The isolates were identified using MALDI-TOF and the antimicrobial susceptibility test was performed using the Kirby-Bauer technique. To characterize the resistance genes, a polymerase chain reaction (PCR) scheme was performed. Of the isolates identified as Gram-negative, 68.8% were Enterobacterales, represented by E. coli, Enterobacter cloacae, Citrobacter spp., and Klebsiella pneumoniae; 28.1% belonged to the genus Acinetobacter spp.; and 3.1% to Pseudomonas aeruginosa. A 9.3% of the isolates were multidrug-resistant (MDR), presenting resistance to antibiotics from three different classes, while 18.8% presented resistance to two or more classes of different antibiotics. The diversity of three genes that code for ESBL (blaTEM, blaCTX-M and blaSHV) was detected in 12.5% of the strains. The most frequent was blaSHV, while blaTEM and blaCTX-M were present in Citrobacter spp. and Klebsiella pneumoniae. These results are an alarm call for veterinarians and their environment and suggest taking measures to prevent the spread of these microorganisms.

Hypopyon Uveitis as a Manifestation of Primary Choroidal Lymphoma.

A 78-year-old female was referred to our hospital due to a decrease of visual acuity in her left eye. On examination, presence of left choroidal folds and subretinal fluid was disclosed. After being misdiagnosed as neovascular age-related macular degeneration treatment with intravitreal injections of Aflibercept was started. Despite improvement of fluid, persistence of choroidal folds encouraged a magnetic resonance imaging revealing a left retrobulbar nodular lesion. Furthermore, development of hypopyon during follow-up allowed a flow cytometry analysis of an aqueous humour sample that confirmed infiltration by a non-Hodgkin mature B-cell lymphoproliferative process. Finally, treatment with Rituximab and intravenous corticosteroids achieved complete resolution. Primary choroidal lymphoma may occur with an atypical presentation, including hypopyon uveitis. Thus, familiarity with its clinical features is fundamental for an early recognition and correct management.

Reabilitação estética com facetas e coroas cerâmicas em dissilicato de lítio: relato de caso / Aesthetic rehabilitation with ceramic facets and crowns in lithium disilicate: case report

Introdução: A procura pela estética do sorriso é crescente na Odontologia, pois, muitas vezes um sorriso alinhado e periodonto saudável não são o bastante. A cerâmica odontológica apresenta-se como uma ótima possibilidade restauradora, visto o avanço das técnicas de adesão entre o substrato dentário e as cerâmicas, torna-se mais previsível o resultado com este tipo de reabilitação. Objetivo: O presente artigo tem como objetivo descrever um caso clínico com envolvimento de diversos níveis de desgaste dentário para reabilitação estética com cerâmica de dissilicato de lítio. Relato de caso: Paciente 36 anos, gênero feminino, apresentava insatisfação com seu sorriso devido a forma e a alteração de cor dos seus dentes superiores anteriores e pré-molares. O plano de tratamento consistiu em realizar a troca da coroa metalocerâmica por coroa total cerâmica da unidade 14, coroa total cerâmica nas unidades 11, 21 e 22, facetas cerâmicas nas unidades 15, 13, 12, 23, 24 e 25, osteotomia e gengivoplastia das regiões de 2º prémolar superior esquerdo ao 2º pré-molar superior direito, clareamento dental caseiro da arcada inferior e placa oclusal superior de proteção. O material de escolha para a resolução do caso clínico foi a cerâmica vítrea reforçada à base de dissilicato de lítio, pois, possui um índice de refração de luz semelhante à estrutura dentária, sem interferência significativa da translucidez, além de ser passível de cimentação adesiva por se tratar de uma cerâmica ácido sensível e o tamanho do cristal e a sua disposição favorecem o aumento das propriedades mecânicas da restauração. Conclusão: O plano de tratamento realizado permitiu o restabelecimento da função e estética, com reprodução das características dos dentes naturais e promoção da jovialidade e da harmonia no sorriso(AU)

Introduction:The demand for smile aesthetics is growing in Dentistry, because, often a smile aligned and healthy periodontium are not enough. Dental ceramics, presented as an excellent restorative possibility, since the advancement of adhesion techniques between the dental substrate and the ceramics, becomes more predictable the result with this type of rehabilitation. Objective: This article aims to describe a clinical case involving several levels of dental wear for aesthetic rehabilitation with ceramics. Case Report: A 36-year-old female patient presented dissatisfaction with her smile due to the shape and color alteration of her anterior and premolar upper teeth. The treatment plan consisted of exchanging the metal-ceramic crown for the total ceramic crown of unit 14, total ceramic crown in units 11, 21 and 22, ceramic veneers in units 15, 13, 12, 23, 24 and 25, osteotomy and gingivoplasty of the regions from 2nd left upper premolar to 2nd right upper premolar, home tooth whitening of the lower arch and upper occlusal plate of protection. The material of choice for the resolution of the clinical case was the glass ceramic reinforced on the basis of lithium disilicate because it has a refractive index of light similar to the dental structure, without significant interference of translucency, besides being liable to adhesive cementation because it is a sensitive acid ceramic and the size of the crystal and its disposition favor the increase of the mechanical properties of the restoration. Conclusion: The treatment plan performed allowed the restoration of function and aesthetics, with reproduction of the characteristics of natural teeth and promotion of joviality and harmony in the smile(AU)

RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease.

RGS14 is a multifunctional scaffolding protein that is highly expressed within postsynaptic spines of pyramidal neurons in hippocampal area CA2. Known roles of RGS14 in CA2 include regulating G protein, H-Ras/ERK, and calcium signaling pathways to serve as a natural suppressor of synaptic plasticity and postsynaptic signaling. RGS14 also shows marked postsynaptic expression in major structures of the limbic system and basal ganglia, including the amygdala and both the ventral and dorsal subdivisions of the striatum. In this review, we discuss the signaling functions of RGS14 and its role in postsynaptic strength (long-term potentiation) and spine structural plasticity in CA2 hippocampal neurons, and how RGS14 suppression of plasticity impacts linked behaviors such as spatial learning, object memory, and fear conditioning. We also review RGS14 expression in the limbic system and basal ganglia and speculate on its possible roles in regulating plasticity in these regions, with a focus on behaviors related to emotion and motivation. Finally, we explore the functional implications of RGS14 in various brain circuits and speculate on its possible roles in certain disease states such as hippocampal seizures, addiction, and anxiety disorders.

Animal models for the study of intracranial hematomas (Review).

Intracranial hematomas (ICH) are a frequent condition in neurosurgical and neurological practices, with several mechanisms of primary and secondary injury. Experimental research has been fundamental for the understanding of the pathophysiology implicated with ICH and the development of therapeutic interventions. To date, a variety of different animal approaches have been described that consider, for example, the ICH evolutive phase, molecular implications and hemodynamic changes. Therefore, choosing a test protocol should consider the scope of each particular study. The present review summarized investigational protocols in experimental research on the subject of ICH. With this subject, injection of autologous blood or bacterial collagenase, inflation of intracranial balloon and avulsion of cerebral vessels were the models identified. Rodents (mice) and swine were the most frequent species used. These different models allowed improvements on the understanding of intracranial hypertension establishment, neuroinflammation, immunology, brain hemodynamics and served to the development of therapeutic strategies.

Functional Assessment of Cancer-Linked Mutations in Sensitive Regions of Regulators of G Protein Signaling Predicted by Three-Dimensional Missense Tolerance Ratio Analysis.

Regulators of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling by acting as negative regulators of G proteins. Genetic variants in RGS proteins are associated with many diseases, including cancers, although the impact of these mutations on protein function is uncertain. Here we analyze the RGS domains of 15 RGS protein family members using a novel bioinformatic tool that measures the missense tolerance ratio (MTR) using a three-dimensional (3D) structure (3DMTR). Subsequent permutation analysis can define the protein regions that are most significantly intolerant (P < 0.05) in each dataset. We further focused on RGS14, RGS10, and RGS4. RGS14 exhibited seven significantly tolerant and seven significantly intolerant residues, RGS10 had six intolerant residues, and RGS4 had eight tolerant and six intolerant residues. Intolerant and tolerant-control residues that overlap with pathogenic cancer mutations reported in the COSMIC cancer database were selected to define the functional phenotype. Using complimentary cellular and biochemical approaches, proteins were tested for effects on GPCR-Gα activation, Gα binding properties, and downstream cAMP levels. Identified intolerant residues with reported cancer-linked mutations RGS14-R173C/H and RGS4-K125Q/E126K, and tolerant RGS14-S127P and RGS10-S64T resulted in a loss-of-function phenotype in GPCR-G protein signaling activity. In downstream cAMP measurement, tolerant RGS14-D137Y and RGS10-S64T and intolerant RGS10-K89M resulted in change of function phenotypes. These findings show that 3DMTR identified intolerant residues that overlap with cancer-linked mutations cause phenotypic changes that negatively impact GPCR-G protein signaling and suggests that 3DMTR is a potentially useful bioinformatics tool for predicting functionally important protein residues. SIGNIFICANCE STATEMENT: Human genetic variant/mutation information has expanded rapidly in recent years, including cancer-linked mutations in regulator of G protein signaling (RGS) proteins. However, experimental testing of the impact of this vast catalogue of mutations on protein function is not feasible. We used the novel bioinformatics tool three-dimensional missense tolerance ratio (3DMTR) to define regions of genetic intolerance in RGS proteins and prioritize which cancer-linked mutants to test. We found that 3DMTR more accurately classifies loss-of-function mutations in RGS proteins than other databases thereby offering a valuable new research tool.

First Evidence of Gastroprotection by Schinus molle: Roles of Nitric Oxide, Prostaglandins, and Sulfhydryls Groups in Its Mechanism of Action.

Schinus molle is a plant traditionally used in Mexico to treat gastric disorders. However, no scientific evidence has been reported on its gastroprotective effect. The aim of the current contribution was to conduct a bioassay-guided study on S. molle to evaluate its gastroprotective activity in a model of Wistar rats given ethanol orally to induce gastric lesions. The hexane and dichloromethane extracts from the tested plant showed over 99% gastroprotection at a dose of 100 mg/kg. From the hexane extract, two of the three fractions (F1 and F2) afforded over 99% gastroprotection. The F1 fraction was subjected to column chromatography, which revealed a white solid. Based on the ESI-MS analysis, the two main compounds in this solid were identified. The predominant compound was probably a triterpene. This mixture of compounds furnished about 67% gastroprotection at a dose of 100 mg/kg. Pretreatment with L-NAME, indomethacin, and NEM was carried out to explore the possible involvement of nitric oxide, prostaglandins, and/or sulfhydryl groups, respectively, in the gastroprotective activity of the white solid. We found evidence for the participation of all three factors. No antisecretory activity was detected (tested by pylorus ligation). In conclusion, evidence is herein provided for the first time of the gastroprotective effect of S. molle.

Restabelecimento estético de incisivos laterais conóides e amplas restaurações em resina composta com laminados cerâmicos: relato de caso / Aesthetic recovering of conoid side incisives and wide restoration in composed resin with ceramic laminates: case report

Introdução: As cerâmicas odontológicas são amplamente utilizadas na Odontologia, desfrutando de grande popularidade devido a sua capacidade de mimetizar as características ópticas do esmalte e da dentina. O constante desenvolvimento de pesquisas tem desencadeado o lançamento de novos sistemas cerâmicos com propriedades aprimoradas e melhores resultados clínicos em longo prazo. Objetivo: O relato de caso aqui apresentado descreve uma reabilitação da zona estética do sorriso com laminados cerâmicos por meio de uma abordagem minimamente invasiva. Relato de caso: Paciente do gênero feminino, compareceu à clínica odontológica relatando insatisfação com a aparência do seu sorriso. Durante avaliação foram observadas, na região anterossuperior, restaurações extensas em resina composta deficientes nos incisivos, com proporção, volume, forma e texturização insatisfatórias, que em conjunto comprometia a zona estética do sorriso. Diante disso, após fotografias extra e intraorais, o tratamento proposto foi a reabilitação com laminados cerâmicos nas unidades 1.2 ao 2.2. Assim, foi realizado o enceramento e o mock-up, os quais serviram de orientação para os preparos dentários, a seguir, foram moldados e as restaurações confeccionadas no sistema IPS e.max. Após prova de cor e adaptação, os preparos e a superfície interna dos laminados cerâmicos foram tratados e cimentados com cimento resino fotopolimerizável. Conclusão: Instituindo uma abordagem conservadora, o plano de tratamento realizado através da reabilitação com laminados cerâmicos nas unidades dentárias anterossuperiores, permitiu o restabelecimento da função e estética, com reprodução das características dos dentes naturais e promoção do equilíbrio, da jovialidade e da harmonia no sorriso(AU)

Introduction: Dental ceramics are widely used in dentistry, enjoying great popularity due to the ability to mimic both enamel and dentin optical characteristics. The constant research development has triggered the launch of new ceramic systems with improved properties and better long-term clinical results. Objective: The case report presented here describes the zone rehabilitation of the aesthetic smile with ceramic laminates through a minimally invasive approach. Case report: Female patient, attended the dental clinic reporting dissatisfaction with the appearance of her smile. During the evaluation, extensive restorations in composite resin were observed in the incisors in the anterosuperior region, with unsatisfactory proportion, amount, shape and texturing, which together compromised the aesthetic zone of the smile. Faced with this, after extra and intraoral photographs, the proposed treatment was the restoration with the ceramic laminates in units 1.2 to 2.2. Thus, waxing and mock-up were performed, which served as guidance for the dental preparations, then they were molded and restorations fabricated in the IPS e.max system. After shade and adaptation proof, the preparations and the inner ceramic laminates surface were treated and cemented with light-cured resin cement. Conclusion: Adopting a conservative approach, the treatment plan carried out through restoration with ceramic laminates on the upper anterior teeth allowed the recovering function and aesthetics, reproducing characteristics of natural teeth and promoting balance, joviality and harmony in the smile(AU)

Prevalence and Risk Factors for Human T-Cell Lymphotropic Virus (HTLV) in Blood Donors in Brazil-A 10-Year Study (2007-2016).

It is unknown whether HTLV-1/2 prevalence has been stable or changing with time in Brazil. We present a 10-year (2007-2016) analysis of HTLV-1/2 infection in first-time blood donors from four blood banks in Brazil. The Brazilian blood centers participating in this multicenter Recipient Epidemiology and Donor Evaluation Study (REDS) are located in Recife in the Northeast and in São Paulo, Rio de Janeiro and Belo Horizonte located in the Southeast of the country. A previous REDS study using the same database from 2007 to 2009 showed that the prevalence per 100,000 donors was 222 in Recife, 83 in Belo Horizonte and 101 in São Paulo. From 2007 to 2016, HTLV-1/2 prevalence was calculated by year, blood center and birth cohort. Covariates included age, gender, schooling, self-reported skin color and type of donation. From 1,092,174 first-blood donations, in the general analysis, HTLV-1/2 infection predominated in females, donors over 50 years of age, black skin color and less educated. The average prevalence was 228 per 100,000 donors in Recife, 222 in Rio de Janeiro, 104 in Belo Horizonte and 103 in São Paulo. In the 10-year analysis, HTLV-1/2 prevalence was stable, but a trend was observed toward an increase in HTLV-1/2 infection among younger people (p < 0.001), males (p = 0.049), those with white skin color (p < 0.001), and higher education (p = 0.014). Therefore, this 10-year surveillance of the infection showed stable HTLV-1/2 prevalence overall but a trend toward increased prevalence among the younger and more educated donors despite Brazilian policies to control sexually transmitted infections being in place for more than 10 years.

RGS14 regulates PTH- and FGF23-sensitive NPT2A-mediated renal phosphate uptake via binding to the NHERF1 scaffolding protein.

Phosphate homeostasis, mediated by dietary intake, renal absorption, and bone deposition, is incompletely understood because of the uncharacterized roles of numerous implicated protein factors. Here, we identified a novel role for one such element, regulator of G protein signaling 14 (RGS14), suggested by genome-wide association studies to associate with dysregulated Pi levels. We show that human RGS14 possesses a carboxy-terminal PDZ ligand required for sodium phosphate cotransporter 2a (NPT2A) and sodium hydrogen exchanger regulatory factor-1 (NHERF1)-mediated renal Pi transport. In addition, we found using isotope uptake measurements combined with bioluminescence resonance energy transfer assays, siRNA knockdown, pull-down and overlay assays, and molecular modeling that secreted proteins parathyroid hormone (PTH) and fibroblast growth factor 23 inhibited Pi uptake by inducing dissociation of the NPT2A-NHERF1 complex. PTH failed to affect Pi transport in cells expressing RGS14, suggesting that it suppresses hormone-sensitive but not basal Pi uptake. Interestingly, RGS14 did not affect PTH-directed G protein activation or cAMP formation, implying a postreceptor site of action. Further pull-down experiments and direct binding assays indicated that NPT2A and RGS14 bind distinct PDZ domains on NHERF1. We showed that RGS14 expression in human renal proximal tubule epithelial cells blocked the effects of PTH and fibroblast growth factor 23 and stabilized the NPT2A-NHERF1 complex. In contrast, RGS14 genetic variants bearing mutations in the PDZ ligand disrupted RGS14 binding to NHERF1 and subsequent PTH-sensitive Pi transport. In conclusion, these findings identify RGS14 as a novel regulator of hormone-sensitive Pi transport. The results suggest that changes in RGS14 function or abundance may contribute to the hormone resistance and hyperphosphatemia observed in kidney diseases.

11ßHSD2 Efficacy in Preventing Transcriptional Activation of the Mineralocorticoid Receptor by Corticosterone.

Affinity of the mineralocorticoid receptor (MR) is similar for aldosterone and the glucocorticoids (GC) cortisol and corticosterone, which circulate at concentrations far exceeding those of aldosterone. 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) inactivation of GC within the immediate vicinity of the MR is credited with prereceptor specificity for aldosterone in cells coexpressing MR and 11ßHSD2. 11ßHSD2 efficacy is also critical to other recently described 11ßHSD2 substrates. The aim of this work was to address doubts that low levels of expression of 11ßHSD2 in aldosterone target tissues suffice to prevent the initiation of gene transcription by the MR activated by physiological concentrations of corticosterone. Cell models stably expressing an MR/Gaussia luciferase reporter and various levels of constitutive or induced 11ßHSD2 at concentrations lower than those in rat kidney homogenates and microsomes were produced. Aldosterone and corticosterone were equipotent transactivators of the MR reporter gene in cells without 11ßHSD2. Rate of conversion of tritiated corticosterone to 11-dehydrocorticosterone increased and corticosterone-induced nuclear translocation of MR decreased, as 11ßHSD2 expression increased. The 50% maximal MR activation for the reporter gene stimulation by corticosterone rose with increasing 11ßHSD2 expression, shifting the steroid dose-response curve for corticosterone-induced MR transactivation to the right. Several stable cell lines expressing an easily and reproducibly measured MR reporter system and consistent incremental amounts of 11ßHSD2 protein were produced and used to document that 11ßHSD2 within low physiological levels inactivates relevant concentrations of GC and decreases MR transactivation by GC in a dose-dependent fashion, laying to rest doubts of the efficacy of this enzyme.

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Introduction and Other Protein Targets.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15537. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Negative Consequences on the Growth, Morphometry, and Community Structure of the Kelp Macrocystis pyrifera (Phaeophyceae, Ochrophyta) by a Short Pollution Pulse of Heavy Metals and PAHs.

The study of pollution effects in the marine environment has become important in recent decades, and the exposure to simultaneous pollutants has become especially relevant. Indeed, the study of key organisms, such as ecosystem engineers, can show a broader view of the effects of pollutants. In this context, we evaluate in situ the effects of a short (7-day) pollution pulse of combined solutions of heavy metals and polycyclic aromatic hydrocarbons (PAHs) (Cu + PAHs, Cd + PAHs, Cu + Cd, and Cu + Cd + PAHs) on the development and morphological features of Macrocystis pyrifera sporophytes over a period of 90 days. Additionally, we determined the effects on the community structure associated with this kelp. This study evidenced a smaller number of blades and a decreased size of blades and holdfasts, as well as the death of individuals exposed to a secondary mix of metals (Cu + Cd) and a tertiary mix of pollutants (Cu + Cd + PAHs). Regarding the effects on the accompanying fauna, low richness and diversity were registered. M. pyrifera grazers, according to the mixture of pollutants, were either absent or diminished. These results show that the pulse of contamination in the early stages of M. pyrifera negatively affects its development and morphometry, as well as its role as an ecosystem engineer, due to a negative alteration in the species composition.

Diet, body weight and pain susceptibility - A systematic review of preclinical studies.

Obesity has been associated with increased chronic pain susceptibility but causes are unclear. In this review, we systematize and analyze pain outcomes in rodent models of obesity as these can be important tools for mechanistic studies. Studies were identified using MEDLINE/PubMed and Scopus databases using the following search query: (((pain) OR (nociception)) AND (obesity)) AND (rat OR (mouse) OR (rodent))). From each eligible record we extracted the following data: species, strain, sex, pain/obesity model and main behavioral readouts. Out of 695 records 33 were selected for inclusion. 27 studies assessed nociception/acute pain and 17 studies assessed subacute or chronic pain. Overall genetic and dietary models overlapped in pain-related outcomes. Most acute pain studies reported either decreased or unaltered responses to noxious painful stimuli. However, decreased thresholds to mechanical innocuous stimuli, i.e. allodynia, were frequently reported. In most studies using subacute and chronic pain models, namely of subcutaneous inflammation, arthritis and perineural inflammation, decreased thresholds and/or prolonged pain manifestations were reported in obesity models. Strain comparisons and longitudinal observations indicate that genetic factors and the time course of the pathology might account for some of the discrepancies observed across studies. Two studies reported increased pain in animals subjected to high fat diet in the absence of weight gain. Pain-related outcomes in experimental models and clinical obesity are aligned indicating that the rodent can be an useful tool to study the interplay between diet, obesity and pain. In both cases weight gain might represent only a minor contribution to abnormal pain manifestation.