RESUMO
Phylogenomics of bats suggests that their echolocation either evolved separately in the bat suborders Yinpterochiroptera and Yangochiroptera, or had a single origin in bat ancestors and was later lost in some yinpterochiropterans1-6. Hearing for echolocation behaviour depends on the inner ear, of which the spiral ganglion is an essential structure. Here we report the observation of highly derived structures of the spiral ganglion in yangochiropteran bats: a trans-otic ganglion with a wall-less Rosenthal's canal. This neuroanatomical arrangement permits a larger ganglion with more neurons, higher innervation density of neurons and denser clustering of cochlear nerve fascicles7-13. This differs from the plesiomorphic neuroanatomy of Yinpterochiroptera and non-chiropteran mammals. The osteological correlates of these derived ganglion features can now be traced into bat phylogeny, providing direct evidence of how Yangochiroptera differentiated from Yinpterochiroptera in spiral ganglion neuroanatomy. These features are highly variable across major clades and between species of Yangochiroptera, and in morphospace, exhibit much greater disparity in Yangochiroptera than Yinpterochiroptera. These highly variable ganglion features may be a neuroanatomical evolutionary driver for their diverse echolocating strategies4,14-17 and are associated with the explosive diversification of yangochiropterans, which include most bat families, genera and species.
Assuntos
Evolução Biológica , Quirópteros , Orelha Interna , Ecolocação , Gânglio Espiral da Cóclea , Animais , Quirópteros/anatomia & histologia , Quirópteros/classificação , Quirópteros/fisiologia , Orelha Interna/anatomia & histologia , Orelha Interna/inervação , Orelha Interna/fisiologia , Ecolocação/fisiologia , Filogenia , Gânglio Espiral da Cóclea/anatomia & histologia , Gânglio Espiral da Cóclea/fisiologiaRESUMO
Immunotoxins (ITs) target cancer cells via antibody binding to surface antigens followed by internalization and toxin-mediated inhibition of protein synthesis. The fate of cells responding to IT treatment depends on the amount and stability of specific pro-apoptotic and pro-survival proteins. When treated with a pseudomonas exotoxin-based immunotoxin (HB21PE40), the triple-negative breast cancer (TNBC) cell line MDA-MB-468 displayed a notable resistance to toxin-mediated killing compared to the epidermoid carcinoma cell line, A431, despite succumbing to the same level of protein synthesis inhibition. In a combination screen of ~1912 clinically relevant and mechanistically annotated compounds, we identified several agents that greatly enhanced IT-mediated killing of MDA-MB-468 cells while exhibiting only a modest enhancement for A431 cells. Of interest, two Smac mimetics, birinapant and SM164, exhibited this kind of differential enhancement. To investigate the basis for this, we probed cells for the presence of inhibitor of apoptosis (IAP) proteins and monitored their stability after the addition of immunotoxin. We found that high levels of IAPs inhibited immunotoxin-mediated cell death. Further, TNFα levels were not relevant for the combination's efficacy. In tumor xenograft studies, combinations of immunotoxin and birinapant caused complete regressions in MDA-MB-468tumor-bearing mice but not in mice with A431 tumors. We propose that IAPs constitute a barrier to immunotoxin efficacy which can be overcome with combination treatments that include Smac mimetics.
Assuntos
Imunotoxinas , Neoplasias , Humanos , Animais , Camundongos , Proteínas Inibidoras de Apoptose/metabolismo , Imunotoxinas/farmacologia , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , ApoptoseRESUMO
BACKGROUND: Through the evolution of novel wing structures, bats (Order Chiroptera) became the only mammalian group to achieve powered flight. This achievement preceded the massive adaptive radiation of bats into diverse ecological niches. We investigate some of the developmental processes that underlie the origin and subsequent diversification of one of the novel membranes of the bat wing: the plagiopatagium, which connects the fore- and hind limb in all bat species. RESULTS: Our results suggest that the plagiopatagium initially arises through novel outgrowths from the body flank that subsequently merge with the limbs to generate the wing airfoil. Our findings further suggest that this merging process, which is highly conserved across bats, occurs through modulation of the programs controlling the development of the periderm of the epidermal epithelium. Finally, our results suggest that the shape of the plagiopatagium begins to diversify in bats only after this merging has occurred. CONCLUSIONS: This study demonstrates how focusing on the evolution of cellular processes can inform an understanding of the developmental factors shaping the evolution of novel, highly adaptive structures.
Assuntos
Quirópteros , Animais , Voo Animal , Mamíferos , Desenvolvimento Embrionário , Asas de AnimaisRESUMO
BACKGROUND AND AIMS: Treatment of hepatocellular carcinomas using our glypican-3 (GPC3)-targeting human nanobody (HN3) immunotoxins causes potent tumor regression by blocking protein synthesis and down-regulating the Wnt signaling pathway. However, immunogenicity and a short serum half-life may limit the ability of immunotoxins to transition to the clinic. APPROACH AND RESULTS: To address these concerns, we engineered HN3-based immunotoxins to contain various deimmunized Pseudomonas exotoxin (PE) domains. This included HN3-T20, which was modified to remove T-cell epitopes and contains a PE domain II truncation. We compared them to our previously reported B-cell deimmunized immunotoxin (HN3-mPE24) and our original HN3-immunotoxin with a wild-type PE domain (HN3-PE38). All of our immunotoxins displayed high affinity to human GPC3, with HN3-T20 having a KD value of 7.4 nM. HN3-T20 retained 73% enzymatic activity when compared with the wild-type immunotoxin in an adenosine diphosphate-ribosylation assay. Interestingly, a real-time cell growth inhibition assay demonstrated that a single dose of HN3-T20 at 62.5 ng/mL (1.6 nM) was capable of inhibiting nearly all cell proliferation during the 10-day experiment. To enhance HN3-T20's serum retention, we tested the effect of adding a streptococcal albumin-binding domain (ABD) and a llama single-domain antibody fragment specific for mouse and human serum albumin. For the detection of immunotoxin in mouse serum, we developed a highly sensitive enzyme-linked immunosorbent assay and found that HN3-ABD-T20 had a 45-fold higher serum half-life than HN3-T20 (326 minutes vs. 7.3 minutes); consequently, addition of an ABD resulted in HN3-ABD-T20-mediated tumor regression at 1 mg/kg. CONCLUSION: These data indicate that ABD-containing deimmunized HN3-T20 immunotoxins are high-potency therapeutics ready to be evaluated in clinical trials for the treatment of liver cancer.
Assuntos
ADP Ribose Transferases/uso terapêutico , Toxinas Bacterianas/uso terapêutico , Carcinoma Hepatocelular/terapia , Exotoxinas/uso terapêutico , Glipicanas/antagonistas & inibidores , Imunotoxinas/uso terapêutico , Neoplasias Hepáticas/terapia , Anticorpos de Domínio Único/uso terapêutico , Fatores de Virulência/uso terapêutico , ADP Ribose Transferases/química , ADP Ribose Transferases/farmacologia , Animais , Toxinas Bacterianas/química , Toxinas Bacterianas/farmacologia , Linhagem Celular Tumoral , Exotoxinas/química , Exotoxinas/farmacologia , Humanos , Imunotoxinas/química , Imunotoxinas/farmacologia , Camundongos , Camundongos Nus , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/farmacologia , Fatores de Virulência/química , Fatores de Virulência/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Exotoxina A de Pseudomonas aeruginosaRESUMO
Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.
Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Éteres/farmacologia , L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/metabolismo , Compostos de Anilina/química , Antineoplásicos/química , Linhagem Celular Tumoral , Éteres/química , Humanos , L-Lactato Desidrogenase/químicaRESUMO
Bats are incredibly diverse, both morphologically and taxonomically. Bats are the only mammalian group to have achieved powered flight, an adaptation that is hypothesized to have allowed them to colonize various and diverse ecological niches. However, the lack of fossils capturing the transition from terrestrial mammal to volant chiropteran has obscured much of our understanding of bat evolution. Over the last 20 years, the emergence of evo-devo in non-model species has started to fill this gap by uncovering some developmental mechanisms at the origin of bat diversification. In this review, we highlight key aspects of studies that have used bats as a model for morphological adaptations, diversification during adaptive radiations, and morphological novelty. To do so, we review current and ongoing studies on bat evolution. We first investigate morphological specialization by reviewing current knowledge about wing and face evolution. Then, we explore the mechanisms behind adaptive diversification in various ecological contexts using vision and dentition. Finally, we highlight the emerging work into morphological novelties using bat wing membranes.
RESUMO
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Therapeutic outcomes of HCC remain unsatisfactory, and novel treatments are urgently needed. GPC3 (glypican-3) is an emerging target for HCC, given the findings that 1) GPC3 is highly expressed in more than 70% of HCC; (2) elevated GPC3 expression is linked with poor HCC prognosis; and (3) GPC3-specific therapeutics, including immunotoxin, bispecific antibody and chimeric antigen receptor T cells. have shown promising results. Here, we postulate that GPC3 is a potential target of antibody-drug conjugates (ADCs) for treating liver cancer. To determine the payload for ADCs against liver cancer, we screened three large drug libraries (> 9,000 compounds) against HCC cell lines and found that the most potent drugs are DNA-damaging agents. Duocarmycin SA and pyrrolobenzodiazepine dimer were chosen as the payloads to construct two GPC3-specific ADCs: hYP7-DC and hYP7-PC. Both ADCs showed potency at picomolar concentrations against a panel of GPC3-positive cancer cell lines, but not GPC3 negative cell lines. To improve potency, we investigated the synergetic effect of hYP7-DC with approved drugs. Gemcitabine showed a synergetic effect with hYP7-DC in vitro and in vivo. Furthermore, single treatment of hYP7-PC induced tumor regression in multiple mouse models. Conclusion: We provide an example of an ADC targeting GPC3, suggesting a strategy for liver cancer therapy.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Glipicanas/antagonistas & inibidores , Imunoconjugados/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Feminino , Humanos , CamundongosRESUMO
Extensive optimization of quinazoline-based lead 8 is described. The structure-activity relationship studies indicate the S-configuration is preferred for the phenylmorpholine substitution. Together with incorporation of a (2-hydroxyl-2-methylpropyl)pyrazole moiety at the 2-position leads to analogs with comparable potency and marked improvement in the pharmacokinetic profile over our previously reported lead compounds. Further in vivo efficacy studies in Kasumi-1 xenograft mouse model demonstrates that the selected inhibitors are well tolerated and highly efficacious in the inhibition of tumor growth. Additionally, the representative analog 19 also demonstrated significant improvement of arthritis severity in a collagen-induced arthritis (CIA) mouse model. These results indicate potential use of these quinazoline-based BET inhibitors for treatment of cancer and inflammatory diseases. A brief discussion of the co-crystallized structure of 19 with BRD4 (BD1) is also highlighted.
Assuntos
Anti-Inflamatórios/química , Antineoplásicos/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Quinazolinas/química , Fatores de Transcrição/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Artrite/tratamento farmacológico , Artrite/patologia , Proteínas de Ciclo Celular/metabolismo , Modelos Animais de Doenças , Meia-Vida , Humanos , Cinética , Camundongos , Neoplasias/tratamento farmacológico , Quinazolinas/farmacocinética , Quinazolinas/uso terapêutico , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismoRESUMO
Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1ß (IL-1ß). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.
Assuntos
Dor Crônica/metabolismo , Inflamassomos/metabolismo , Microglia/metabolismo , Morfina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuralgia/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Animais , Dor Crônica/patologia , Dor Crônica/fisiopatologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Interleucina-1beta/metabolismo , Masculino , Microglia/patologia , Neuralgia/patologia , Neuralgia/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/patologia , Corno Dorsal da Medula Espinal/fisiopatologiaRESUMO
Mammals have highly diverse limbs that have contributed to their occupation of almost every niche. Researchers have long been investigating the development of these diverse limbs, with the goals of identifying developmental processes and potential biases that shape mammalian limb diversity. To date, researchers have used techniques ranging from the genomic to the anatomic to investigate the developmental processes shaping the limb morphology of mammals from five orders (Marsupialia, Chiroptera, Rodentia, Cetartiodactyla, and Perissodactyla). Results of these studies suggest that the differential expression of genes controlling diverse cellular processes underlies mammalian limb diversity. Results also suggest that the earliest development of the limb tends to be conserved among mammalian species, while later limb development tends to be more variable. This research has established the mammalian limb as a model system for evolutionary developmental biology, and set the stage for more in-depth, cross-disciplinary research into the genetic controls, tissue-level cellular behaviors, and selective pressures that have driven the developmental evolution of mammalian limbs. Ideally, these studies will be performed in a diverse suite of mammalian species within a comparative, phylogenetic framework.
Assuntos
Evolução Biológica , Extremidades , Mamíferos , Animais , Biodiversidade , Mamíferos/anatomia & histologia , Mamíferos/classificação , Modelos Biológicos , TempoRESUMO
In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics.
Assuntos
Desenho de Fármacos , Terapia de Alvo Molecular/métodos , Engenharia de Proteínas/métodos , Receptores Acoplados a Proteínas G/agonistas , Animais , Regulação da Expressão Gênica , Humanos , Ligantes , Mutação , Receptores Acoplados a Proteínas G/biossíntese , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/efeitos dos fármacos , Pesquisa Translacional BiomédicaRESUMO
A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.
Assuntos
Proteínas Nucleares/antagonistas & inibidores , Quinazolinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Sítios de Ligação , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Proteínas Nucleares/química , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacocinética , Relação Estrutura-Atividade , Fatores de Transcrição/químicaRESUMO
The neuromodulator dopamine signals through the dopamine D2 receptor (D2R) to modulate central nervous system functions through diverse signal transduction pathways. D2R is a prominent target for drug treatments in disorders where dopamine function is aberrant, such as schizophrenia. D2R signals through distinct G-protein and ß-arrestin pathways, and drugs that are functionally selective for these pathways could have improved therapeutic potential. How D2R signals through the two pathways is still not well defined, and efforts to elucidate these pathways have been hampered by the lack of adequate tools for assessing the contribution of each pathway independently. To address this, Evolutionary Trace was used to produce D2R mutants with strongly biased signal transduction for either the G-protein or ß-arrestin interactions. These mutants were used to resolve the role of G proteins and ß-arrestins in D2R signaling assays. The results show that D2R interactions with the two downstream effectors are dissociable and that G-protein signaling accounts for D2R canonical MAP kinase signaling cascade activation, whereas ß-arrestin only activates elements of this cascade under certain conditions. Nevertheless, when expressed in mice in GABAergic medium spiny neurons of the striatum, the ß-arrestin-biased D2R caused a significant potentiation of amphetamine-induced locomotion, whereas the G protein-biased D2R had minimal effects. The mutant receptors generated here provide a molecular tool set that should enable a better definition of the individual roles of G-protein and ß-arrestin signaling pathways in D2R pharmacology, neurobiology, and associated pathologies.
Assuntos
Arrestinas/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Modelos Moleculares , Receptores de Dopamina D2/metabolismo , Animais , Arrestinas/química , Corpo Estriado/citologia , Cristalografia , Proteínas de Ligação ao GTP/química , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Mutagênese , Neurônios/metabolismo , Conformação Proteica , Receptores de Dopamina D2/química , Receptores de Dopamina D2/genética , Análise de Regressão , beta-ArrestinasRESUMO
Multiple mammalian lineages independently evolved a definitive mammalian middle ear (DMME) through breakdown of Meckel's cartilage (MC). However, the cellular and molecular drivers of this evolutionary transition remain unknown for most mammal groups. Here, we identify such drivers in the living marsupial opossum Monodelphis domestica, whose MC transformation during development anatomically mirrors the evolutionary transformation observed in fossils. Specifically, we link increases in cellular apoptosis and TGF-BR2 signalling to MC breakdown in opossums. We demonstrate that a simple change in TGF-ß signalling is sufficient to inhibit MC breakdown during opossum development, indicating that changes in TGF-ß signalling might be key during mammalian evolution. Furthermore, the apoptosis that we observe during opossum MC breakdown does not seemingly occur in mouse, consistent with homoplastic DMME evolution in the marsupial and placental lineages.
Assuntos
Ossículos da Orelha/anatomia & histologia , Orelha Média/anatomia & histologia , Arcada Osseodentária/anatomia & histologia , Animais , Evolução Biológica , Fósseis , Mamíferos , Camundongos , Monodelphis , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
DREADDs, designer receptors exclusively activated by designer drugs, are engineered G protein-coupled receptors (GPCR) which can precisely control GPCR signaling pathways (for example, Gq, Gs, and Gi). This chemogenetic technology for control of GPCR signaling has been successfully applied in a variety of in vivo studies, including in mice, to remotely control GPCR signaling, for example, in neurons, glia cells, pancreatic ß-cells, or cancer cells. In order to fully explore the in vivo applications of the DREADD technology, we generated hM3Dq and hM4Di strains of mice which allow for Cre recombinase-mediated restricted expression of these pathway-selective DREADDs. With the many Cre driver lines now available, these DREADD lines will be applicable to studying a wide array of research and preclinical questions. genesis 54:439-446, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Marcação de Genes/métodos , Receptores Acoplados a Proteínas G/metabolismo , Animais , Células Cultivadas , Integrases/genética , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Ligação ProteicaRESUMO
BACKGROUND: Apolipoprotein E-deficient (ApoE(-/-)) rodents spontaneously develop severe hypercholesterolemia and increased aortic stiffness, both accepted risk factors for cardiovascular morbidity and mortality in humans. In patients with resistant hypertension renal denervation (RDN) may improve arterial stiffness, however the underlying mechanisms are incompletely understood. This study investigates the impact of RDN on aortic compliance in a novel atherosclerosis prone ApoE(-/-)-rat model. METHODS: Normotensive, 8 weeks old ApoE(-/-) and Sprague-Dawley (SD) rats were subjected to bilateral surgical RDN (n = 6 per group) or sham operation (n = 5 per group) and fed with normal chow for 8 weeks. Compliance of the ascending aorta was assessed by magnetic resonance imaging. Vasomotor function was measured by aortic ring tension recordings. Aortic collagen content was quantified histologically and plasma aldosterone levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: After 8 weeks, ApoE(-/-)-sham demonstrated a 58 % decrease in aortic distensibility when compared with SD-sham (0.0051 ± 0.0011 vs. 0.0126 ± 0.0023 1/mmHg; p = 0.02). This was accompanied by an impaired endothelium-dependent relaxation of aortic rings and an increase in aortic medial fibrosis (17.87 ± 1.4 vs. 12.27 ± 1.1 %; p = 0.006). In ApoE(-/-)-rats, RDN prevented the reduction of aortic distensibility (0.0128 ± 0.002 vs. 0.0051 ± 0.0011 1/mmHg; p = 0.01), attenuated endothelial dysfunction, and decreased aortic medial collagen content (12.71 ± 1.3 vs. 17.87 ± 1.4 %; p = 0.01) as well as plasma aldosterone levels (136.33 ± 6.6 vs. 75.52 ± 8.4 pg/ml; p = 0.0003). Cardiac function and metabolic parameters such as hypercholesterolemia were not influenced by RDN. CONCLUSION: ApoE(-/-)-rats spontaneously develop impaired vascular compliance. RDN improves aortic distensibility and attenuated endothelial dysfunction in ApoE(-/-)-rats. This was associated with a reduction in aortic fibrosis formation, and plasma aldosterone levels.
Assuntos
Aorta/fisiopatologia , Apolipoproteínas E/deficiência , Aterosclerose/fisiopatologia , Denervação , Rim/inervação , Sistema Nervoso Simpático/fisiopatologia , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Apolipoproteínas E/metabolismo , Aterosclerose/patologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Carbacol/farmacologia , Progressão da Doença , Endotélio Vascular/fisiopatologia , Fibrose , Testes de Função Cardíaca , Técnicas In Vitro , Inflamação/patologia , Rim/fisiopatologia , Nitroglicerina/farmacologia , Norepinefrina/metabolismo , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/patologia , Vasodilatação/efeitos dos fármacosAssuntos
Pelve Renal/cirurgia , Laparoscopia , Fenômenos Magnéticos , Stents , Ureter/cirurgia , Anastomose Cirúrgica/instrumentação , Anastomose Cirúrgica/métodos , Animais , Desenho de Equipamento , Feminino , Estudo de Prova de Conceito , Suínos , Porco Miniatura , Procedimentos Cirúrgicos Urológicos/instrumentação , Procedimentos Cirúrgicos Urológicos/métodosRESUMO
In this work, we report for the first time that Na-ion intercalation of reduced graphene oxide (RGO) can significantly improve its printed network's performance as a transparent conductor. Unlike pristine graphene that inhibits Na-ion intercalation, the larger layer-layer distance of RGO allows Na-ion intercalation, leading to simultaneously much higher DC conductivity and higher optical transmittance. The typical increase of transmittance from 36% to 79% and decrease of sheet resistance from 83k to 311 Ohms/sq in the printed network was observed after Na-ion intercalation. Compared with Li-intercalated graphene, Na-ion intercalated RGO shows much better environmental stability, which is likely due to the self-terminating oxidation of Na ions on the RGO edges. This study demonstrated the great potential of metal-ion intercalation to improve the performance of printed RGO network for transparent conductor applications.
RESUMO
An essential aspect of episodic memory is the formation of associations between neutral sensory cues in the environment. In light of recent evidence that this critical aspect of learning does not require the hippocampus, we tested the involvement of the retrosplenial cortex (RSC) in this process using a chemogenetic approach that allowed us to temporarily silence neurons along the entire rostrocaudal extent of the RSC. A viral vector containing the gene for a synthetic inhibitory G-protein-coupled receptor (hM4Di) was infused into RSC. When the receptor was later activated by systemic injection of clozapine-N-oxide, neural activity in RSC was transiently silenced (confirmed using a patch-clamp procedure). Rats expressing hM4Di and control rats were trained in a sensory preconditioning procedure in which a tone and light were paired on some trials and a white noise stimulus was presented alone on the other trials during the Preconditioning phase. Thus, rats were given the opportunity to form an association between a tone and a light in the absence of reinforcement. Later, the light was paired with food. During the test phase when the auditory cues were presented alone, controls exhibited more conditioned responding during presentation of the tone compared with the white noise reflecting the prior formation of a tone-light association. Silencing RSC neurons during the Preconditioning phase prevented the formation of an association between the tone and light and eliminated the sensory preconditioning effect. These findings indicate that RSC may contribute to episodic memory formation by linking essential sensory stimuli during learning.
Assuntos
Aprendizagem por Associação/fisiologia , Córtex Cerebral/fisiologia , Condicionamento Psicológico/fisiologia , Neurônios/fisiologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Clozapina/análogos & derivados , Clozapina/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Sinais (Psicologia) , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Long-EvansRESUMO
AIMS: Sympathetic stimulation induces left ventricular hypertrophy and is associated with increased cardiovascular risk. Catheter-based renal denervation (RDN) has been shown to reduce sympathetic outflow and blood pressure (BP). The present multi-centre study aimed to investigate the effect of RDN on anatomic and functional myocardial parameters, assessed by cardiac magnetic resonance (CMR), in patients with resistant hypertension. METHODS AND RESULTS: Cardiac magnetic resonance was performed in 72 patients (mean age 66 ± 10 years) with resistant hypertension (55 patients underwent RDN, 17 served as controls) at baseline and after 6 months. Clinical data and CMR results were analysed blindly. Renal denervation significantly reduced systolic and diastolic BP by 22/8 mm Hg and left ventricular mass index (LVMI) by 7.1% (46.3 ± 13.6 g/m(1.7) vs. 43.0 ± 12.6 g/m(1.7), P < 0.001) without changes in the control group (41.9 ± 10.8 g/m(1.7) vs. 42.0 ± 9.7 g/m(1.7), P = 0.653). Ejection fraction (LVEF) in patients with impaired LVEF at baseline (<50%) significantly increased after RDN (43% vs. 50%, P < 0.001). Left ventricular circumferential strain as a surrogate of diastolic function in the subgroup of patients with reduced strain at baseline increased by 21% only in the RDN group (-14.8 vs. -17.9; P = 0.001) and not in control patients (-15.5 vs. -16.4, P = 0.508). CONCLUSIONS: Catheter-based RDN significantly reduced BP and LVMI and improved EF and circumferential strain in patients with resistant hypertension, occurring partly BP independently.