Central Regulation of Pituitary-Thyroid Axis Under Physiological and Pathophysiological Conditions.

TRH is a tripeptide amide that functions as a neurotransmitter but also serves as a neurohormone that has a critical role in the central regulation of the hypothalamic-pituitary-thyroid axis. Hypophysiotropic TRH neurons involved in this neuroendocrine process are located in the hypothalamic paraventricular nucleus and secrete TRH into the pericapillary space of the external zone of the median eminence for conveyance to anterior pituitary thyrotrophs. Under basal conditions, the activity of hypophysiotropic TRH neurons is regulated by the negative feedback effects of thyroid hormone to ensure stable, circulating, thyroid hormone concentrations, a mechanism that involves complex interactions between hypophysiotropic TRH neurons and the vascular system, cerebrospinal fluid, and specialized glial cells called tanycytes. Hypophysiotropic TRH neurons also integrate other humoral and neuronal inputs that can alter the setpoint for negative feedback regulation by thyroid hormone. This mechanism facilitates adaptation of the organism to changing environmental conditions, including the shortage of food and a cold environment. The thyroid axis is also affected by other adverse conditions such as infection, but the central mechanisms mediating suppression of hypophysiotropic TRH may be pathophysiological. In this review, we discuss current knowledge about the mechanisms that contribute to the regulation of hypophysiotropic TRH neurons under physiological and pathophysiological conditions

Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents

There is increasing evidence that local thyroid hormone (TH) availability changes profoundly in inflammatory conditions due to altered expression of deiodinases that metabolize TH. It is largely unknown, however, how inflammation affects TH availability via the expression of TH transporters. In this study we examined the effect of bacterial lipopolysaccharide (LPS) administration on two TH transporters that are critically important for brain TH homeostasis, organic anion-transporting polypeptide 1c1 (OATP1c1) and monocarboxylate transporter 8 (MCT8). Messenger RNA levels were studied by in situ hybridization and quantitative PCR, and protein levels by immunofluorescence in both the rat and mouse forebrain. The mRNA of both transporters decreased robustly in the first 9h after LPS injection, selectively in brain blood vessels; OATP1c1 mRNA in astrocytes and MCT8 mRNA in neurons remained unchanged. At 24 and/or 48h after LPS administration, OATP1c1 and MCT8 mRNAs increased markedly above control levels in brain vessels. OATP1c1 protein decreased markedly in vessels by 24h, whereas MCT8 protein levels did not decrease significantly. These changes were highly similar in mice and rats. The data demonstrate that OATP1c1 and MCT8 expression are regulated in a parallel manner during inflammation at the blood-brain barrier of rodents. Given the indispensable role of both transporters in allowing TH access to the brain, the results suggest reduced brain TH uptake during systemic inflammation

Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances

The hypothalamic melanocortin system is crucial for the control of appetite and body weight. Two of the five melanocortin receptors, MC3R and MC4R are involved in hypothalamic control of energy homeostasis, with the MC4R having the major influence. It is generally thought that the main impact of the melanocortin system on hypothalamic circuits is external to the arcuate nucleus, and that any effect locally in the arcuate nucleus is inhibitory on proopiomelanocortin-expressing (POMC) neurons. In contrast, using current- and voltage-clamp recordings from identified neurons, we demonstrate that MC3R and MC4R agonists depolarize arcuate POMC neurons and a separate arcuate neuronal population identified by the rat insulin 2 promoter (RIPCre) transgene expression. Furthermore, the endogenous MC3R and MC4R antagonist, agouti-related protein (AgRP), hyperpolarizes POMC and RIPCre neurons in the absence of melanocortin agonist, consistent with inverse agonism at the MC4R. A decreased transient outward (I(A)) potassium conductance, and to a lesser extent the inward rectifier (K(IR)) conductance, underlies neuronal depolarization, whereas an increase in I(A) mediates AgRP-induced hyperpolarization. Accordingly, POMC and RIPCre neurons may be targets for peptide transmitters that are possibly released locally from AgRP-expressing and POMC neurons in the arcuate nucleus, adding further previously unappreciated complexity to the arcuate system

Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells

Hypothyroidism in humans is characterized by severe neurological consequences that are often irreversible, highlighting the critical role of thyroid hormone (TH) in the brain. Despite this, not much is known about the signaling pathways that control TH action in the brain. What is known is that the prohormone thyroxine (T4) is converted to the active hormone triiodothyronine (T3) by type 2 deiodinase (D2) and that this occurs in astrocytes, while TH receptors and type 3 deiodinase (D3), which inactivates T3, are found in adjacent neurons. Here, we modeled TH action in the brain using an in vitro coculture system of D2-expressing H4 human glioma cells and D3-expressing SK-N-AS human neuroblastoma cells. We found that glial cell D2 activity resulted in increased T3 production, which acted in a paracrine fashion to induce T3-responsive genes, including ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), in the cocultured neurons. D3 activity in the neurons modulated these effects. Furthermore, this paracrine pathway was regulated by signals such as hypoxia, hedgehog signaling, and LPS-induced inflammation, as evidenced both in the in vitro coculture system and in in vivo rat models of brain ischemia and mouse models of inflammation. This study therefore presents what we believe to be the first direct evidence for a paracrine loop linking glial D2 activity to TH receptors in neurons, thereby identifying deiodinases as potential control points for the regulation of TH signaling in the brain during health and disease.NIHFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Hungarian Scientific Research FundHungarian Academy of SciencesUniv Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USAUniversidade Federal de São Paulo, Mol Endocrinol Lab, Div Endocrinol, Dept Med, São Paulo, BrazilHungarian Acad Sci, Inst Expt Med, Lab Endocrine Neurobiol, Budapest, HungaryBrigham & Womens Hosp, Thyroid Sect, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USATufts Med Ctr, Div Endocrinol Diabet & Metab, Dept Med, Tupper Res Inst, Boston, MA USATufts Univ, Sch Med, Dept Neurosci, Boston, MA 02111 USAUniversidade Federal de São Paulo, Mol Endocrinol Lab, Div Endocrinol, Dept Med, São Paulo, BrazilNIH: DK77086NIH: DK37021FAPESP: 05/55825-8FAPESP: 05/55826-4Hungarian Scientific Research Fund: OTKA K81226Web of Scienc

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Arranjos contratuais e incentivos à qualidade na cadeia da carne bovina no estado de São Paulo : uma análise de confiança

Orientadora: Profª. Drª. Sandra Mara de Alencar SchiaviCoorientadora: Profª. Drª. Aleksan ShanoyanTese (Doutorado em Administração) - Universidade Estadual de Maringá, 2020RESUMO: A confiança é vista como elemento importante nas relações econômicas, sendo tema de interesse de estudos de diversas disciplinas. A presente tese explora o conceito de confiança sob o enfoque da Nova Economia Institucional e da Nova Sociologia Econômica. Embora ambos aportes teóricos tenham trazido avanços para predizer como as transações são desenvolvidas, acredita-se que a teoria possa ser expandida, principalmente quando empregada sob enfoque integrado. Especialmente ao se considerar Sistemas Agroindustriais (SAG), falhas de coordenação podem causar ineficiências e comprometer a competitividade dos agentes. Adotou-se como objetivo analisar a influência da confiança na qualidade do ativo transacionado e nos arranjos contratuais. A análise se deu no SAG da carne bovina, mais especificamente nas transações entre pecuaristas e frigoríficos localizados no interior do Estados de São Paulo. A escolha por tal objeto se deve ao fato das exigências por qualidade e segurança do alimento na cadeia da carne bovina terem aumentado significativamente nos últimos anos, o que exige dos agentes capacidade de adoção de mecanismos que possam estimular investimentos e garantir a qualidade da carne ao longo da cadeia. Ademais, o SAG da carne bovina apresenta falhas de coordenação, que têm comprometido o desenvolvimento desse setor. Alguns estudos apontam a ausência de transparência e a adoção de comportamento oportunista como fatores preponderantes para falta de estímulo a investimentos em qualidade por parte dos agentes (pecuaristas) a montante da cadeia, resultando em perda de competividade. Nesse sentido, a confiança entre os agentes é vista como um mecanismo que pode reduzir comportamento oportunista e as falhas decorrentes de assimetria de informação, incentivando, consequentemente, investimentos em qualidade por parte dos pecuaristas e a adoção de determinados arranjos contratuais. Diante disto, evidencia-se a necessidade do entendimento da confiança como mecanismo de incentivo à qualidade. Este estudo apresenta como proposição teórica a tese de que a confiança influencia a qualidade do ativo transacionado e o arranjo contratual. Para atingir o objetivo proposto empregou-se uma abordagem quantitativa, por meio de dois estudos. O primeiro deles, fez uso de banco de dados fornecido por uma empresa de consultoria em agronegócios, que continha dados de 1314 transações entre pecuaristas e frigoríficos. Para o estudo 2, os dados primários foram coletados por meio de questionário semiestruturado aplicado face-a-face a 127 pecuaristas do estado de São Paulo. Para a análise dos dados, empregou-se as técnicas análise de componentes principais, regressão linear múltipla, regressão logística e moderação. Os resultados permitem confirmar a proposição teórica ao demonstrar que a confiança incentiva investimentos em qualidade e os ativos de alta qualidade tendem a serem transacionados pelo arranjo contratual de peso morto. Portanto, confiança antecede a qualidade e serve como mecanismo de incentivo ao sinalizar que os investimentos serão recompensados, mesmo sob um arranjo contratual que ofereça vulnerabilidade e risco de apropriação de valor. Observou-se também que o tamanho da propriedade do pecuarista está relacionado com a qualidade do ativo. Grandes pecuaristas tendem a transacionar produtos de maior qualidade pelo arranjo contratual de peso morto. Outro achado importante está na identificação de um fenômeno nomeado no presente estudo como "inversão de agência" e sua predição com base na qualidade do ativo transacionado. Por fim, este estudo traz contribuições gerenciais ao identificar que para alcançar o nível de qualidade almejado pelo mercado demandante, a indústria frigorífica deve ampliar a transparência nas transações, sinalizando aos pecuaristas que os investimentos em qualidade serão recompensados.ABSTRACT: Trust is seen as an important element in economic relations, being a topic of interest in studies of different disciplines. This thesis explores the concept of trust under the New Institutional Economics and New Economic Sociology approaches. Although both theoretical contributions have brought advances to predict how transactions are developed, it is believed that the theory can be expanded, especially when used under an integrated perspective. Especially when considering Agroindustrial Systems (SAG), coordination failures can cause inefficiencies and compromise the competitiveness of agents. The objective was to analyze the influence of trust in the quality of the asset traded and in the contractual arrangements. The analysis took place in the SAG of beef, more specifically in the transactions between cattleman and slaughterhouses located in the interior of the States of São Paulo. The choice for this object is due to the fact that the demands for quality and food safety in the beef chain have increased significantly in recent years, which requires agents to be able to adopt mechanisms that can stimulate investments and guarantee the quality of the meat along the chain. In addition, the SAG for beef presents coordination failures, which have compromised the development of this sector. Some studies point to the lack of transparency and the adoption of opportunistic behavior as major factors for the lack of incentive for investment in quality by upstream agents (cattlemen), resulting in a loss of competitiveness. In this sense, trust between agents is seen as a mechanism that can reduce opportunistic behavior and failures resulting from information asymmetry, consequently encouraging investment in quality on the part of ranchers and the adoption of certain contractual arrangements. Thus, the need to understand trust as a mechanism to encourage quality is evident. The theoretical proposition in this thesis is that trust influences the quality of the traded asset and determines the contractual arrangement. To achieve the objective, a quantitative approach was used, through two studies. The first one made use of a database provided by an agribusiness consulting company, with data on 1314 transactions between cattlemen and slaughterhouses. For study 2, primary data were collected using a semi-structured questionnaire applied face-to-face to 127 cattlemen in the state of São Paulo. For data analysis, principal component analysis, multiple linear regression, logistic regression and moderation techniques were used. The results allow to confirm the theoretical proposition by demonstrating that trust encourages investments in quality and high-quality assets tend to be traded under the contractual arrangement of deadweight. Therefore, trust precedes quality and serves as an incentive mechanism in signaling that investments will be rewarded, even under a contractual arrangement that offers vulnerability and risk of value appropriation. It was also observed that the size of the rancher is related to the quality of the asset. Larger cattlemen tend to trade higher quality products through the contractual arrangement of deadweight. Another important finding is the identification of a phenomenon named in the present study as "agency inversion" and its prediction based on the quality of the traded asset. Finally, this study brings managerial contributions by identifying that to reach the level of quality desired by the demanding market, the slaughterhouse industry must increase transparency in transactions, signaling to cattlemen that investments in quality will be rewarded.131 f. : il. color., figs., tabs., maps