RESUMEN
This empirical research on children's poverty and the accompanying risk behavior was conducted in the Baktalórántháza micro-region, in one of the most disadvantaged micro-regions of Hungary. The study, completed in 2023, was conducted utilizing three methods, a questionnaire for families, interviews, and focus group interviews with social professionals working in the settlements. The region is one of the ten micro-regions with the highest poverty rate in the country. The majority of the population only has an elementary education, and the proportion of graduates is much lower than the national average. The proportion of households with three or more children is higher than the national average and the proportion of unemployed people in households with children is twice as high as the national average. Based on the experience of social workers working in the area, in addition to smoking and drinking alcohol, the consumption of psychoactive and psychotropic substances has increased among adolescents and young adults. Based on various indicators, children regularly consume illegal drugs. The origin and composition of these drugs are typically unknown. According to the reports by drug users, everyday life is easier, and they can escape from problems when under the influence of drugs. Based on the observations of experts, the consumption of various psychoactive substances has harmful effects on behavior, health, learning, and family life. School performance and the ability to think and learn decrease. Drug users are dissatisfied with their lives, have problems with social relationships, engage in partner violence, and may develop antisocial behavior in their lives.
RESUMEN
The mineralocorticoid receptor (MR) is a transcription factor for genes mediating diverse, cell-specific functions, including trophic effects as well as promoting fluid/electrolyte homeostasis. It was reported that in intercalated cells, phosphorylation of the MR at serine 843 (S843) by Unc-51-like kinase (ULK1) inhibits MR activation and that phosphorylation of ULK1 by mechanistic target of rapamycin (mTOR) inactivates ULK1, and thereby prevents MR inactivation. We extended these findings with studies in M1 mouse cortical collecting duct cells stably expressing the rat MR and a reporter gene. Pharmacological inhibition of ULK1 dose-dependently increased ligand-induced MR transactivation, while ULK1 activation had no effect. Pharmacological inhibition of mTOR and CRISPR/gRNA gene knockdown of rapamycin-sensitive adapter protein of mTOR (Raptor) or rapamycin-insensitive companion of mTOR (Rictor) decreased phosphorylated ULK1 and ligand-induced activation of the MR reporter gene, as well as transcription of endogenous MR-target genes. As predicted, ULK1 inhibition had no effect on aldosterone-mediated transcription in M1 cells with the mutated MR-S843A (alanine cannot be phosphorylated). In contrast, mTOR inhibition dose-dependently decreased transcription in the MR-S843A cells, though not as completely as in cells with the wild-type MR-S843. mTOR, Raptor, and Rictor coprecipitated with the MR and addition of aldosterone increased their phosphorylated, active state. These results suggest that mTOR significantly regulates MR activity in at least 2 ways: by suppressing MR inactivation by ULK1, and by a yet ill-defined mechanism that involves direct association with MR. They also provide new insights into the diverse functions of ULK1 and mTOR, 2 key enzymes that monitor the cell's energy status.
Asunto(s)
Aldosterona , Receptores de Mineralocorticoides , Animales , Ratones , Ratas , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Ligandos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Complejos Multiproteicos/metabolismo , Fosforilación , Proteína Asociada al mTOR Insensible a la Rapamicina/metabolismo , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Proteína Reguladora Asociada a mTOR , ARN Guía de Sistemas CRISPR-Cas , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Biotic homogenization-increasing similarity of species composition among ecological communities-has been linked to anthropogenic processes operating over the last century. Fossil evidence, however, suggests that humans have had impacts on ecosystems for millennia. We quantify biotic homogenization of North American mammalian assemblages during the late Pleistocene through Holocene (~30,000 ybp to recent), a timespan encompassing increased evidence of humans on the landscape (~20,000-14,000 ybp). From ~10,000 ybp to recent, assemblages became significantly more homogenous (>100% increase in Jaccard similarity), a pattern that cannot be explained by changes in fossil record sampling. Homogenization was most pronounced among mammals larger than 1 kg and occurred in two phases. The first followed the megafaunal extinction at ~10,000 ybp. The second, more rapid phase began during human population growth and early agricultural intensification (~2,000-1,000 ybp). We show that North American ecosystems were homogenizing for millennia, extending human impacts back ~10,000 years.
Asunto(s)
Biodiversidad , Extinción Biológica , Fósiles , Mamíferos , Agricultura , Animales , Tamaño Corporal , Ecosistema , Humanos , América del Norte , Crecimiento DemográficoRESUMEN
A hallmark of type 2 diabetes (T2D) is hepatic resistance to insulin's glucose-lowering effects. The serum- and glucocorticoid-regulated family of protein kinases (SGK) is activated downstream of mechanistic target of rapamycin complex 2 (mTORC2) in response to insulin in parallel to AKT. Surprisingly, despite an identical substrate recognition motif to AKT, which drives insulin sensitivity, pathological accumulation of SGK1 drives insulin resistance. Liver-specific Sgk1-knockout (Sgk1Lko) mice display improved glucose tolerance and insulin sensitivity and are protected from hepatic steatosis when fed a high-fat diet. Sgk1 promotes insulin resistance by inactivating AMP-activated protein kinase (AMPK) via phosphorylation on inhibitory site AMPKαSer485/491. We demonstrate that SGK1 is dominant among SGK family kinases in regulation of insulin sensitivity, as Sgk1, Sgk2, and Sgk3 triple-knockout mice have similar increases in hepatic insulin sensitivity. In aggregate, these data suggest that targeting hepatic SGK1 may have therapeutic potential in T2D.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Inmediatas-Precoces/metabolismo , Hígado/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Animales , Diabetes Mellitus Tipo 2/patología , Dieta Alta en Grasa , Proteína Forkhead Box O1/metabolismo , Glucosa/metabolismo , Proteínas Inmediatas-Precoces/deficiencia , Proteínas Inmediatas-Precoces/genética , Insulina/metabolismo , Resistencia a la Insulina , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Guía de Kinetoplastida/metabolismo , Transducción de SeñalRESUMEN
Cities and agricultural fields encroach on the most fertile, habitable terrestrial landscapes, fundamentally altering global ecosystems. Today, 75% of terrestrial ecosystems are considerably altered by human activities, and landscape transformation continues to accelerate. Human impacts are one of the major drivers of the current biodiversity crisis, and they have had unprecedented consequences on ecosystem function and rates of species extinctions for thousands of years. Here we use the fossil record to investigate whether changes in geographic range that could result from human impacts have altered the climatic niches of 46 species covering six mammal orders within the contiguous United States. Sixty-seven percent of the studied mammals have significantly different climatic niches today than they did before the onset of the Industrial Revolution. Niches changed the most in the portions of the range that overlap with human-impacted landscapes. Whether by forcible elimination/introduction or more indirect means, large-bodied dietary specialists have been extirpated from climatic envelopes that characterize human-impacted areas, whereas smaller, generalist mammals have been facilitated, colonizing these same areas of the climatic space. Importantly, the climates where we find mammals today do not necessarily represent their past habitats. Without mitigation, as we move further into the Anthropocene, we can anticipate a low standing biodiversity dominated by small, generalist mammals.
Asunto(s)
Agricultura , Distribución Animal , Clima , Fósiles , Mamíferos , Urbanización , Animales , Tamaño Corporal , Conservación de los Recursos Naturales , Dieta , Ecosistema , Humanos , Factores de Tiempo , Estados UnidosRESUMEN
Recent renewed interest in using fossil data to understand how biotic interactions have shaped the evolution of life is challenging the widely held assumption that long-term climate changes are the primary drivers of biodiversity change. New approaches go beyond traditional richness and co-occurrence studies to explicitly model biotic interactions using data on fossil and modern biodiversity. Important developments in three primary areas of research include analysis of (i) macroevolutionary rates, (ii) the impacts of and recovery from extinction events, and (iii) how humans (Homo sapiens) affected interactions among non-human species. We present multiple lines of evidence for an important and measurable role of biotic interactions in shaping the evolution of communities and lineages on long timescales.
Asunto(s)
Biodiversidad , Fósiles , Evolución Biológica , Cambio ClimáticoRESUMEN
Drugs of abuse cause significant neuroadaptations within the ventral tegmental area (VTA), with alterations in gene expression tied to changes in reward behavior. Serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription, catalytic activity, and phosphorylation are upregulated in the VTA by chronic cocaine or morphine treatment, positioning SGK1 as a critical mediator of reward behavior. Using transgenic mouse models, we investigated the effect of SGK1 knockout in the VTA and in dopamine (DA) neurons to evaluate the necessity of protein expression for natural and drug reward behaviors. SGK1 knockdown in the VTA did not impact reward behaviors. Given VTA cellular heterogeneity, we also investigated a DA neuron-specific SGK1 knockout (KO). DA SGK1 KO significantly decreased body weight of adult mice as well as increased general locomotor activity; however, reward behaviors were similarly unaltered. Given that SGK1 mutants virally overexpressed in the VTA are capable of altering drug-associated behavior, our current results suggest that changes in SGK1 protein signaling may be distinct from expression. This work yields novel information on the impact of SGK1 deletion, critical for understanding the role of SGK1 signaling in the central nervous system and evaluating SGK1 as a potential therapeutic target for treatment of substance use disorders.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Proteínas Inmediatas-Precoces/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Recompensa , Área Tegmental Ventral/efectos de los fármacos , Animales , Inhibidores de Captación de Dopamina/farmacología , Neuronas Dopaminérgicas/patología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Área Tegmental Ventral/patologíaRESUMEN
Large mammals are at high risk of extinction globally. To understand the consequences of their demise for community assembly, we tracked community structure through the end-Pleistocene megafaunal extinction in North America. We decomposed the effects of biotic and abiotic factors by analyzing co-occurrence within the mutual ranges of species pairs. Although shifting climate drove an increase in niche overlap, co-occurrence decreased, signaling shifts in biotic interactions. Furthermore, the effect of abiotic factors on co-occurrence remained constant over time while the effect of biotic factors decreased. Biotic factors apparently played a key role in continental-scale community assembly before the extinctions. Specifically, large mammals likely promoted co-occurrence in the Pleistocene, and their loss contributed to the modern assembly pattern in which co-occurrence frequently falls below random expectations.
Asunto(s)
Ecosistema , Extinción Biológica , Fósiles , Mamíferos , Animales , Cambio Climático , América del Norte , Paleontología , Dinámica PoblacionalRESUMEN
Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan. Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.
Asunto(s)
Envejecimiento/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/fisiología , Membranas Mitocondriales/fisiología , Animales , Autofagia/fisiología , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/fisiología , Restricción Calórica , Células HEK293 , Humanos , Longevidad/fisiología , Masculino , Ratones , Ratones Noqueados , Mitocondrias , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Permeabilidad , Cultivo Primario de Células , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Daño por Reperfusión/metabolismo , Transducción de SeñalRESUMEN
Nitrones (e.g. α-phenyl-N-tert-butyl nitrone; PBN) are cerebroprotective in experimental stroke. Free radical trapping is their proposed mechanism. As PBN has low radical trapping potency, we tested Sgk1 induction as another possible mechanism. PBN was injected (100 mg/kg, i.p.) into adult male rats and mice. Sgk1 was quantified in cerebral tissue by microarray, quantitative RT-PCR and western analyses. Sgk1+/+ and Sgk1-/- mice were randomized to receive PBN or saline immediately following transient (60 min) occlusion of the middle cerebral artery. Neurological deficit was measured at 24 h and 48 h and infarct volume at 48 h post-occlusion. Following systemic PBN administration, rapid induction of Sgk1 was detected by microarray (at 4 h) and confirmed by RT-PCR and phosphorylation of the Sgk1-specific substrate NDRG1 (at 6 h). PBN-treated Sgk1+/+ mice had lower neurological deficit ( p < 0.01) and infarct volume ( p < 0.01) than saline-treated Sgk1+/+ mice. PBN-treated Sgk1-/- mice did not differ from saline-treated Sgk1-/- mice. Saline-treated Sgk1-/- and Sgk1+/+ mice did not differ. Brain Sgk3:Sgk1 mRNA ratio was 1.0:10.6 in Sgk1+/+ mice. Sgk3 was not augmented in Sgk1-/- mice. We conclude that acute systemic treatment with PBN induces Sgk1 in brain tissue. Sgk1 may play a part in PBN-dependent actions in acute brain ischemia.
Asunto(s)
Óxidos N-Cíclicos/uso terapéutico , Proteínas Inmediatas-Precoces/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Animales , Encéfalo/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Óxidos N-Cíclicos/farmacología , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/farmacología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Masculino , Ratones , Ratones Noqueados , Óxidos de Nitrógeno/farmacología , Óxidos de Nitrógeno/uso terapéutico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/farmacología , Ratas , Accidente Cerebrovascular/tratamiento farmacológico , Activación Transcripcional/efectos de los fármacosRESUMEN
Although the central nervous system has been implicated in glucocorticoid-induced gain of fat mass, the underlying mechanisms are poorly understood. The aim of this study was to investigate the possible involvement of hypothalamic serum- and glucocorticoid-regulated kinase 1 (SGK1) in glucocorticoid-increased adiposity. It is well known that SGK1 expression is induced by acute glucocorticoid treatment, but it is interesting that we found its expression to be decreased in the arcuate nucleus of the hypothalamus, including proopiomelanocortin (POMC) neurons, following chronic dexamethasone (Dex) treatment. To study the role of SGK1 in POMC neurons, we produced mice that developed or experienced adult-onset SGK1 deletion in POMC neurons (PSKO). As observed in Dex-treated mice, PSKO mice exhibited increased adiposity and decreased energy expenditure. Mice overexpressing constitutively active SGK1 in POMC neurons consistently had the opposite phenotype and did not experience Dex-increased adiposity. Finally, Dex decreased hypothalamic α-melanocyte-stimulating hormone (α-MSH) content and its precursor Pomc expression via SGK1/FOXO3 signaling, and intracerebroventricular injection of α-MSH or adenovirus-mediated FOXO3 knockdown in the arcuate nucleus largely reversed the metabolic alterations in PSKO mice. These results demonstrate that POMC SGK1/FOXO3 signaling mediates glucocorticoid-increased adiposity, providing new insights into the mechanistic link between glucocorticoids and fat accumulation and important hints for possible treatment targets for obesity.
Asunto(s)
Adiposidad/efectos de los fármacos , Dexametasona/farmacología , Proteína Forkhead Box O3/genética , Glucocorticoides/farmacología , Proteínas Inmediatas-Precoces/genética , Neuronas/efectos de los fármacos , Proopiomelanocortina/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Adiposidad/genética , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Metabolismo Energético/efectos de los fármacos , Proteína Forkhead Box O3/metabolismo , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Proteínas Inmediatas-Precoces/metabolismo , Masculino , Ratones , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , alfa-MSH/efectos de los fármacos , alfa-MSH/metabolismoRESUMEN
Sodium deficiency increases angiotensin II (ATII) and aldosterone, which synergistically stimulate sodium retention and consumption. Recently, ATII-responsive neurons in the subfornical organ (SFO) and aldosterone-sensitive neurons in the nucleus of the solitary tract (NTSHSD2 neurons) were shown to drive sodium appetite. Here we investigate the basis for NTSHSD2 neuron activation, identify the circuit by which NTSHSD2 neurons drive appetite, and uncover an interaction between the NTSHSD2 circuit and ATII signaling. NTSHSD2 neurons respond to sodium deficiency with spontaneous pacemaker-like activity-the consequence of "cardiac" HCN and Nav1.5 channels. Remarkably, NTSHSD2 neurons are necessary for sodium appetite, and with concurrent ATII signaling their activity is sufficient to produce rapid consumption. Importantly, NTSHSD2 neurons stimulate appetite via projections to the vlBNST, which is also the effector site for ATII-responsive SFO neurons. The interaction between angiotensin signaling and NTSHSD2 neurons provides a neuronal context for the long-standing "synergy hypothesis" of sodium appetite regulation.
Asunto(s)
Aldosterona/fisiología , Angiotensina II/fisiología , Relojes Biológicos/fisiología , Neuronas/fisiología , Transducción de Señal , Sodio/fisiología , Núcleo Solitario/fisiología , Animales , Ingestión de Alimentos/fisiología , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/fisiología , Masculino , Ratones , Ratones Transgénicos , Canal de Sodio Activado por Voltaje NAV1.5/fisiología , Vías Nerviosas/fisiología , Núcleos Septales/fisiología , Sodio/deficienciaRESUMEN
The mineralocorticoid receptor (MR) is a member of the steroid-thyroid hormone receptor superfamily of ligand-dependent transcription factors with diverse functions including the biological actions of aldosterone. Identification of the various transcriptional coregulators of MR is essential for understanding the complexity of MR signaling pathways under physiological and pathological conditions. We used a yeast two-hybrid system to find proteins that interact with a full-length MR and found, among other proteins, that MR interacted specifically with receptor for activated C kinase 1 (RACK1), a scaffolding protein. Overexpression of RACK1 using a tetracycline-inducible lentivirus in mouse cortical collecting duct M1 cells stably expressing the rat MR and a Gaussia luciferase gene reporter under a hormone-response element promoter resulted in enhanced agonist-dependent MR transactivation. Knockdown of RACK1 protein expression by short hairpin RNAs led to a significant reduction in MR activation of the reporter gene and the endogenous genes Ctla2α and Psca. We also demonstrated that RACK1 regulation of MR action is mediated through phosphorylation by the PKC-ß signaling pathway. MR and RACK1 were coimmunoprecipitated using an MR antibody in male Sprague-Dawley brain tissue and M1-rMR cells, and colocalization in M1-rMR cells and male rat brains was confirmed by immunofluorescence and immunohistochemistry. The scaffolding protein RACK1 is associated with MR under basal and agonist-stimulated conditions and facilitates agonist-stimulated MR actions through PKC-ß. These findings indicate that RACK1 is a newly described coactivator of MR.
Asunto(s)
Aldosterona/metabolismo , Proteínas de Unión al GTP/metabolismo , Receptores de Mineralocorticoides/metabolismo , Animales , Células Cultivadas , Proteínas de Unión al GTP/genética , Masculino , Regiones Promotoras Genéticas , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores de Cinasa C Activada , Receptores de Mineralocorticoides/genética , Transducción de Señal/genética , Activación TranscripcionalRESUMEN
A major focus in evolutionary biology is to understand how the evolution of organisms relates to changes in their physical environment. In the terrestrial realm, the interrelationships among climate, vegetation, and herbivores lie at the heart of this question. Here we introduce and test a scoring scheme for functional traits present on the worn surfaces of large mammalian herbivore teeth to capture their relationship to environmental conditions. We modeled local precipitation, temperature, primary productivity, and vegetation index as functions of dental traits of large mammal species in 13 national parks in Kenya over the past 60 y. We found that these dental traits can accurately estimate local climate and environment, even at small spatial scales within areas of relatively uniform climate (within two ecoregions), and that they predict limiting conditions better than average conditions. These findings demonstrate that the evolution of key functional properties of organisms may be more reflective of demands during recurring adverse episodes than under average conditions or during isolated severe events.
RESUMEN
OBJECTIVE: Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms. APPROACH AND RESULTS: Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury. MMRKO reduced intima area and intima/media ratio, Ki67- and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67- and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-ß and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages. CONCLUSIONS: Selective deletion of MR in myeloid cells limits macrophage accumulation and vascular inflammation and, therefore, inhibits neointimal hyperplasia and vascular remodeling. Mechanistically, MR deficiency suppresses migration and proliferation of macrophages and leads to less vascular smooth muscle cell activation. At the molecular level, MR deficiency suppresses macrophage inflammatory response via SGK1-AP1/NF-κB pathways.
Asunto(s)
Proteínas Inmediatas-Precoces/metabolismo , Inflamación/enzimología , Macrófagos/enzimología , Músculo Liso Vascular/enzimología , Miocitos del Músculo Liso/enzimología , FN-kappa B/metabolismo , Neointima , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Mineralocorticoides/deficiencia , Factor de Transcripción AP-1/metabolismo , Lesiones del Sistema Vascular/enzimología , Animales , Movimiento Celular , Proliferación Celular , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Arteria Femoral/enzimología , Arteria Femoral/lesiones , Arteria Femoral/metabolismo , Predisposición Genética a la Enfermedad , Hiperplasia , Proteínas Inmediatas-Precoces/genética , Inflamación/genética , Inflamación/patología , Inflamación/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/lesiones , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Comunicación Paracrina , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Células RAW 264.7 , Interferencia de ARN , Receptores de Mineralocorticoides/genética , Transducción de Señal , Factores de Tiempo , Transfección , Remodelación Vascular , Lesiones del Sistema Vascular/genética , Lesiones del Sistema Vascular/patología , Lesiones del Sistema Vascular/prevención & controlRESUMEN
Understanding how ecological communities are organized and how they change through time is critical to predicting the effects of climate change. Recent work documenting the co-occurrence structure of modern communities found that most significant species pairs co-occur less frequently than would be expected by chance. However, little is known about how co-occurrence structure changes through time. Here we evaluate changes in plant and animal community organization over geological time by quantifying the co-occurrence structure of 359,896 unique taxon pairs in 80 assemblages spanning the past 300 million years. Co-occurrences of most taxon pairs were statistically random, but a significant fraction were spatially aggregated or segregated. Aggregated pairs dominated from the Carboniferous period (307 million years ago) to the early Holocene epoch (11,700 years before present), when there was a pronounced shift to more segregated pairs, a trend that continues in modern assemblages. The shift began during the Holocene and coincided with increasing human population size and the spread of agriculture in North America. Before the shift, an average of 64% of significant pairs were aggregated; after the shift, the average dropped to 37%. The organization of modern and late Holocene plant and animal assemblages differs fundamentally from that of assemblages over the past 300 million years that predate the large-scale impacts of humans. Our results suggest that the rules governing the assembly of communities have recently been changed by human activity.
Asunto(s)
Agricultura/historia , Ecosistema , Actividades Humanas/historia , Fenómenos Fisiológicos de las Plantas , Animales , Historia Antigua , Humanos , América del Norte , Dinámica Poblacional , Factores de TiempoRESUMEN
Insulin resistance is a major hallmark of metabolic syndromes, including Type 2 diabetes. Although numerous functions of SGK1 (serum- and glucocorticoid-regulated kinase 1) have been identified, a direct effect of SGK1 on insulin sensitivity has not been previously reported. In the present study, we generated liver-specific SGK1-knockout mice and found that these mice developed glucose intolerance and insulin resistance. We also found that insulin signalling is enhanced or impaired in Hep1-6 cells infected with adenoviruses expressing SGK1 (Ad-SGK1) or shRNA directed against the coding region of SGK1 (Ad-shSGK1) respectively. In addition, we determined that SGK1 inhibits ERK1/2 (extracellular-signal-regulated kinase 1/2) activity in liver and Ad-shERK1/2-mediated inhibition of ERK1/2 reverses the attenuated insulin sensitivity in Ad-shSGK1 mice. Finally, we found that SGK1 functions are compromised under insulin-resistant conditions and overexpression of SGK1 by Ad-SGK1 significantly ameliorates insulin resistance in both glucosamine-treated HepG2 cells and livers of db/db mice, a genetic model of insulin resistance.