Suppression of black-hole growth by strong outflows at redshifts 5.8-6.6.

Bright quasars, powered by accretion onto billion-solar-mass black holes, already existed at the epoch of reionization, when the Universe was 0.5-1 billion years old1. How these black holes formed in such a short time is the subject of debate, particularly as they lie above the correlation between black-hole mass and galaxy dynamical mass2,3 in the local Universe. What slowed down black-hole growth, leading towards the symbiotic growth observed in the local Universe, and when this process started, has hitherto not been known, although black-hole feedback is a likely driver4. Here we report optical and near-infrared observations of a sample of quasars at redshifts 5.8 ≲ z ≲ 6.6. About half of the quasar spectra reveal broad, blueshifted absorption line troughs, tracing black-hole-driven winds with extreme outflow velocities, up to 17% of the speed of light. The fraction of quasars with such outflow winds at z ≳ 5.8 is ≈2.4 times higher than at z ≈ 2-4. We infer that outflows at z ≳ 5.8 inject large amounts of energy into the interstellar medium and suppress nuclear gas accretion, slowing down black-hole growth. The outflow phase may then mark the beginning of substantial black-hole feedback. The red optical colours of outflow quasars at z ≳ 5.8 indeed suggest that these systems are dusty and may be caught during an initial quenching phase of obscured accretion5.

Rapidly star-forming galaxies adjacent to quasars at redshifts exceeding 6.

The existence of massive (1011 solar masses) elliptical galaxies by redshift z ≈ 4 (refs 1, 2, 3; when the Universe was 1.5 billion years old) necessitates the presence of galaxies with star-formation rates exceeding 100 solar masses per year at z > 6 (corresponding to an age of the Universe of less than 1 billion years). Surveys have discovered hundreds of galaxies at these early cosmic epochs, but their star-formation rates are more than an order of magnitude lower. The only known galaxies with very high star-formation rates at z > 6 are, with one exception, the host galaxies of quasars, but these galaxies also host accreting supermassive (more than 109 solar masses) black holes, which probably affect the properties of the galaxies. Here we report observations of an emission line of singly ionized carbon ([C ii] at a wavelength of 158 micrometres) in four galaxies at z > 6 that are companions of quasars, with velocity offsets of less than 600 kilometres per second and linear offsets of less than 100 kiloparsecs. The discovery of these four galaxies was serendipitous; they are close to their companion quasars and appear bright in the far-infrared. On the basis of the [C ii] measurements, we estimate star-formation rates in the companions of more than 100 solar masses per year. These sources are similar to the host galaxies of the quasars in [C ii] brightness, linewidth and implied dynamical mass, but do not show evidence for accreting supermassive black holes. Similar systems have previously been found at lower redshift. We find such close companions in four out of the twenty-five z > 6 quasars surveyed, a fraction that needs to be accounted for in simulations. If they are representative of the bright end of the [C ii] luminosity function, then they can account for the population of massive elliptical galaxies at z ≈ 4 in terms of the density of cosmic space.

Influence of dietary fat and carbohydrates proportions on plasma lipids, glucose control and low-grade inflammation in patients with type 2 diabetes-The TOSCA.IT Study.

PURPOSE: The optimal macronutrient composition of the diet for the management of type 2 diabetes is debated, particularly with regard to the ideal proportion of fat and carbohydrates. The aim of the study was to explore the association of different proportions of fat and carbohydrates of the diet-within the ranges recommended by different guidelines-with metabolic risk factors. METHODS: We studied 1785 people with type 2 diabetes, aged 50-75, enrolled in the TOSCA.IT Study. Dietary habits were assessed using a validated food-frequency questionnaire (EPIC). Anthropometry, fasting lipids, HbA1c and C-reactive protein (CRP) were measured. RESULTS: Increasing fat intake from <25 to ≥35 % is associated with a significant increase in LDL-cholesterol, triglycerides, HbA1c and CRP (p < 0.05). Increasing carbohydrates intake from <45 to ≥60 % is associated with significantly lower triglycerides, HbA1c and CRP (p < 0.05). A fiber intake ≥15 g/1000 kcal is associated with a better plasma lipids profile and lower HbA1c and CRP than lower fiber consumption. A consumption of added sugars of ≥10 % of the energy intake is associated with a more adverse plasma lipids profile and higher CRP than lower intake. CONCLUSIONS: In people with type 2 diabetes, variations in the proportion of fat and carbohydrates of the diet, within the relatively narrow ranges recommended by different nutritional guidelines, significantly impact on the metabolic profile and markers of low-grade inflammation. The data support the potential for reducing the intake of fat and added sugars, preferring complex, slowly absorbable, carbohydrates.

Sex differences in food choices, adherence to dietary recommendations and plasma lipid profile in type 2 diabetes - The TOSCA.IT study.

BACKGROUND AND AIMS: Diabetic women have a more adverse plasma lipid profile than men. Sex differences in dietary habits may play a role, but are little investigated. The study evaluates the quality of diet, adherence to the nutritional recommendations of the Diabetes and Nutrition Study Group and their relation with plasma lipid in men and women with diabetes. METHODS AND RESULTS: We studied 2573 people, aged 50-75, enrolled in the TOSCA.IT study (clinicaltrials.gov; NCT00700856). Plasma lipids were measured centrally. Diet was assessed with a semi-quantitative food frequency questionnaire. Women had a more adverse plasma lipid profile than men. Women consumed significantly more legumes, vegetables, fruits, eggs, milk, vegetable oils, and added sugar, whereas men consumed more starchy foods, soft drinks and alcoholic beverages. This stands for a higher proportion (%) of energy intake from saturated fat and added sugar (12.0 ± 2.4 vs 11.5 ± 2.5 and 3.4 ± 3.2 vs 2.3 ± 3.2, P < 0.04), and a higher intake of fiber (11.2 ± 2.8 vs 10.4 ± 2.6 g/1000 Kcal/day) in women. Adherence to the recommendations for saturated fat and fiber consumption was associated with significantly lower LDL-cholesterol regardless of sex. Adherence to the recommendations for added sugars was associated with significantly lower triglycerides and higher HDL-cholesterol in men and women. CONCLUSIONS: Men and women with diabetes show significant differences in adherence to nutritional recommendations, but sex differences in plasma lipid profile are unlikely to be explained by nutritional factors. Adherence to the nutritional recommendations is associated with a better plasma lipid profile regardless of sex, thus reinforcing the importance of substituting saturated for unsaturated fat sources, increasing fiber and reducing added sugar intake.

Pharmacological characterization of the human melatonin Mel1a receptor following stable transfection into NIH3T3 cells.

1. Mouse fibroblasts (NIH3T3) transfected with the full-length coding region of the Mel1a melatonin receptor stably expressed the receptor, coupled to a pertussis toxin-sensitive G-protein(s) and exhibiting high affinity and adequate pharmacological profile. 2. The receptor protein had the tendency of a strong coupling to the G-protein and therefore low-affinity state was induced by uncoupling the receptor from its G-protein in presence of high concentrations of NaCl (500-700 mM) and/or GTPgammaS (100 microM). Thereafter, the affinity of a series of melatonin analogues was determined to both, high- and low-affinity receptor states, thus providing a basis for the prediction of their efficacy, according to the ternary complex model. 3. The cells were subsequently used to study the agonist-induced G-protein activation, determined by calculating the rate of GDP-GTP exchange measured in presence of 35S-labelled GTPgammaS. The natural ligand melatonin induced a significant increase in the GDP-GTP exchange rate, the presence of GDP and NaCl being necessary to observe this effect. 4. The full agonists 2-phenylmelatonin, 2-bromomelatonin and 6-chloromelatonin equally induced an increase of the GDP-GTP exchange. 5-Hydroxy-N-acetyltryptamine activated the GTP-GDP exchange to a much lesser extent (53%) than melatonin, thus behaving as a partial agonist. As predicted by the model, the melatonin antagonist (N-[(2-phenyl-1H-indol-3-yl)ethyl]cyclobutanecarboxamide) was without effect on basal G protein activation. Coincubation of this compound with melatonin induced a dose-dependent rightward shift in the melatonin concentration-effect curve, thus exhibiting the behaviour of a competitive and surmountable antagonist. 5. Using the equation proposed by Venter (1997) we were able to determine that there were no 'spare' receptors in the system. Therefore, the approach proposed in the present work can be successfully used for the determination of 'drug action' at the level of the human Mel1a melatonin receptor and evaluation of the efficacy of new selective melatonin analogues.

The inducible cyclic adenosine monophosphate early repressor (ICER) in the pituitary intermediate lobe: role in the stress response.

The cAMP signalling pathway plays a key role in the regulation of the hypothalamic-pituitary-adrenal axis. Transcription factor CREM (cAMP response element modulator) is implicated in the modulation of a number of neuroendocrine functions. By virtue of an alternative, intronic promoter CREM generates the powerful transcriptional repressor ICER (inducible cAMP early repressor), which displays a pronounced neuroendocrine-specific expression. Here we document a remarkable induction of ICER in response to acute stress in the intermediate lobe (IL) of the pituitary gland. The induction is transient and is preceded by CREB phosphorylation. Adrenergic stimulation directs ICER induction in the IL through the activation of both beta2-adrenergic and corticotrophin-releasing hormone receptors. These receptors are positively coupled to the adenylate cyclase signalling pathway, which regulates hormone release from the IL, implicating ICER in the modulation of peptide secretion. We show that targeted ablation of the CREM gene in the mouse causes a chronic increase of beta-endorphin levels. Altered hormonal production occurs both in basal conditions and after stress. Thus, early ICER induction in the IL may be involved in the modulation of gene expression in response to stress.

The melatonin receptor in the human brain: cloning experiments and distribution studies.

The adult human cerebellum expresses melatonin receptors with high density in the external zone of the molecular layer. Cloning of the receptor cDNA isolated by RT-PCR from human cerebellar specimens and sequencing analysis of the full-length coding region revealed that the receptor protein is encoded by a transcript identical to that recently cloned from the human hypothalamus (Mel1a). In situ hybridization using an antisense cRNA-probe demonstrated that the melatonin receptor mRNA is localized in the cerebellar granule cells. Mapping of the messenger by RT-PCR with Mel1a specific primers in different areas of the human brain disclosed a quite widespread distribution of the transcript, although expressed at very low levels. Semi-quantitative comparison between the different brain regions allowed to establish the following relative mRNA abundance: cerebellum > or = occipital cortex > or = parietal cortex > temporal cortex > thalamus > frontal cortex > or = hippocampus. No mRNA was detected in white blood cells.

Ras-related and MAPK signalling in neuronal plasticity and memory formation.

Ras-related guanosine triphosphatases (GTPases) couple receptor activity to a number of intracellular signalling events culminating in the control of cell morphology and gene transcription. In culture cells, the best-understood Ras-dependent signalling pathway involves the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) cascade. A growing body of evidence has recently been accumulating to suggest a crucial role of Ras and MAPK signalling in neuronal functions connected to synaptic plasticity. In the present review article we discuss the experimental basis supporting the notion that the Ras/MAPK pathway interacts with other synaptic mechanisms to regulate invertebrate and vertebrate behavioural responses such as those implicated in learning and memory processes.

Differential binding of the NFE3 and CP1/NFY transcription factors to the human gamma- and epsilon-globin CCAAT boxes.

Naturally occurring nondeletional mutations affecting the distal CCAAT box of the human gamma-globin gene promoter result in hereditary persistence of fetal hemoglobin in adult life. Although the distal CCAAT box is the target of several factors, including CP1/NFY, CDP, GATA-1 and NFE3, only NFE3 binding activity is consistently sensitive to well characterized mutations in this region such as G-117-->A, C-114-->T, and delta 13 hereditary persistence of fetal hemoglobin. We extensively characterized the binding specificities of NFE3 and demonstrated that NFE3 has unique properties with respect to other CCAAT box-binding proteins. Affinity-purified NFE3 from erythroid K562 cells binds the distal but not the proximal human gamma-globin CCAAT box, the single CCAAT box of the human epsilon-globin promoter, and the proximal CCAAT box of the evolutionarily related Galago crassicaudatus gamma-globin gene. Within the epsilon-globin CCAAT box, NFE3 represents the major and almost exclusive binding activity. Disruption of such a binding site essentially inactivates the epsilon-globin promoter, suggesting that NFE3 plays an important role in the embryonic expression of this gene.