ABSTRACT We present two-dimensional hydrodynamical simulations for the evolution of early-type galaxies containing central massive black holes (MBHs), starting at an age of . The code contains ...accurate and physically consistent radiative and mechanical active galactic nucleus (AGN) wind feedback, with parsec-scale central resolution. Mass input comes from stellar evolution; energy input includes Type Ia (SNIa) and II supernovae and stellar heating; star formation (SF) is included. Realistic, axisymmetric dynamical galaxy models are built solving the Jeans' equations. The lowest mass models ( ) develop global outflows sustained by SNIa heating, ending with a lower amount of hot gas and new stars. In more massive models, nuclear outbursts last to the present epoch, with large and frequent fluctuations in nuclear emission and from the gas ( ). Each burst lasts years, during which cold, inflowing, and hot, outflowing gas phases coexist. The relation for the gas matches that of local galaxies. AGN activity causes positive feedback for SF. Roughly half of the total mass loss is recycled into new stars ( ), just 3% of it is accreted on the MBH, the remainder being ejected from the galaxy. The ratio between the mass of gas expelled to that in new stars, the load factor, is . Rounder galaxy shapes lead to larger final MBH masses, , and . Almost all of the time is spent at very low nuclear luminosities, yet one quarter of the total energy is emitted at an Eddington ratio . The duty-cycle of AGN activity is approximately 4%.
Over the last two decades, the study of the relationship between
and
in shaping human behavior has encountered a renewed interest. Behavioral genetics showed that distinct polymorphisms of genes that ...code for proteins that control neurotransmitter metabolic and synaptic function are associated with individual vulnerability to aversive experiences, such as stressful and traumatic life events, and may result in an increased risk of developing psychopathologies associated with violence. On the other hand, recent studies indicate that experiencing aversive events modulates gene expression by introducing stable changes to DNA without modifying its sequence, a mechanism known as "epigenetics". For example, experiencing adversities during periods of maximal sensitivity to the environment, such as prenatal life, infancy and early adolescence, may introduce lasting epigenetic marks in genes that affect maturational processes in brain, thus favoring the emergence of dysfunctional behaviors, including exaggerate aggression in adulthood. The present review discusses data from recent research, both in humans and animals, concerning the epigenetic regulation of four genes belonging to the neuroendocrine, serotonergic and oxytocinergic pathways-Nuclear receptor subfamily 3-group C-member 1 (
), oxytocin receptor (
), solute carrier-family 6 member 4 (
) and monoamine oxidase A (
)-and their role in modulating vulnerability to proactive and reactive aggressive behavior. Behavioral genetics and epigenetics are shedding a new light on the fine interaction between genes and environment, by providing a novel tool to understand the molecular events that underlie aggression. Overall, the findings from these studies carry important implications not only for neuroscience, but also for social sciences, including ethics, philosophy and law.
Over the last two decades, it has become increasingly evident that control of aggressive behavior is modulated by the individual genetic profile as well. Several candidate genes have been proposed to ...play a role in the risk to develop antisocial behavior, and distinct brain imaging studies have shown that specific cortical areas may be functionally and/or structurally impaired in impulsive violent subjects on the basis of their genotypes. In this paper, we review the findings regarding four polymorphisms-MAOA (Monoamine oxidase A) uVNTR, SLC6A4 (solute carrier family 6 (neurotransmitter transporter), member 4) 5HTTLPR, COMT (Catechol-O-methyltransferase) Val158Met and DRD4 (dopamine D4 receptor) VNTR 1-11-that all have been found to be associated with an increased vulnerability for antisocial and impulsive behavior in response to aversive environmental conditions. These results, however, have not been replicated by other studies, likely because of crucial methodological discrepancies, including variability in the criteria used to define antisocial behavior and assessment of environmental factors. Finally, it has been recently proposed that these genetic variants may actually increase the individual susceptibility not merely to the negative environmental factors, but to the positive ones as well. In this view, such alleles would play a wider modulatory role, by acting as "plasticity" rather than "vulnerability" genes. Overall, these findings have potential important implications that span well outside of neuroscience and psychiatry, to embrace ethics, philosophy, and the law itself, as they pose new challenges to the very notion of Free Will. Novel properly controlled studies that examine multi-allelic genetic profiles, rather than focusing on distinct single variants, will make it possible to achieve a clearer understanding of the molecular underpinnings of the nature by nurture interaction.
A recent determination of the relationships between the X-ray luminosity of the ISM (LX) and the stellar and total mass for a sample of nearby early-type galaxies (ETGs) is used to investigate the ...origin of the hot gas, via a comparison with the results of hydrodynamical simulations of the ISM evolution for a large set of isolated ETGs. After the epoch of major galaxy formation (after z 2), the ISM is replenished by stellar mass losses and SN ejecta, at the rate predicted by stellar evolution, and is depleted by star formation; it is heated by the thermalization of stellar motions, SNe explosions, and the mechanical (from winds) and radiative AGN feedback. The models agree well with the observed relations, even for the largely different LX values at the same mass, thanks to the sensitivity of the gas flow to many galaxy properties; this holds for models including AGN feedback, and those without. Therefore, the mass input from the stellar population is able to account for a major part of the observed LX; and AGN feedback, while very important to maintain massive ETGs in a time-averaged quasi-steady state, keeping low star formation and the black hole mass, does not dramatically alter the gas content originating in stellar recycled material. These conclusions are based on theoretical predictions for the stellar population contributions in mass and energy, and on a self-consistent modeling of AGN feedback.
•Anger is activated by provocation, and is couched in distinct internal states propagating and escalating in a positive feedback loop. (Fig. 1).•Four left lateralized neural networks that orchestrate ...feeling components were activated during anger induction (Fig. 2).•Anger linguistic expressions convey feeling components that are mapped on neural networks underlying emotional activation and self-regulation.
This review of the neuroscience of anger is part of The Human Affectome Project, where we attempt to map anger and its components (i.e., physiological, cognitive, experiential) to the neuroscience literature (i.e., genetic markers, functional imaging of human brain networks) and to linguistic expressions used to describe anger feelings. Given the ubiquity of anger in both its normative and chronic states, specific language is used in humans to express states of anger. Following a review of the neuroscience literature, we explore the language that is used to convey angry feelings, as well as metaphors reflecting inner states of anger experience. We then discuss whether these linguistic expressions can be mapped on to the neural circuits during anger experience and to distinct components of anger. We also identify relationships between anger components, brain networks, and other affective research relevant to motivational states of dominance and basic needs for safety.
The authors of these article's series have applied several variegated strategies to identify either pleiotropic or unique genes in psychiatric diseases: whole-genome sequencing to identify specific ...mutations in affected families (Han et al.); a candidate gene approach to identify variants associated with overlapping psychiatric diseases (Ma et al.) or to identify shared risk genes in overlapping traits (Unger et al.); analyses of different methylation (Bainomugisa et al.) or transcriptomic (Garrett et al.) patterns; the use of large genome-wide association study (GWAS) datasets from PGC to calculate polygenic risk scores (PRSs) associated with comorbid traits (Swart et al.; Sumner et al.). The authors recruited children with ADHD, ASD, or ADHD plus ASD diagnosis (three clinical groups) and two control groups (community control group of typically developing boys and constructed matched pseudo-control from ADHD family) for genetic analyses of SHANK2 and SHANK3 genes, assessed using Tag-SNPs (single nucleotide polymorphisms). ...Garrett et al. investigated the pathophysiology of PTSD by analyzing blood differential gene expression in three separated trauma-exposed cohorts, and then performed a meta-analysis. ...this Research Topic—collection of articles—reports evidence of novel genes and pathways with pleiotropic effects in several psychiatric disorders, including ADHD, ASD, PTSD, MDD, as well as in migraine and phonological impairments.
Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss ...post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs.
Denosumab is a monoclonal antibody blocking the receptor activator of nuclear factor kappa-B/receptor activator of nuclear factor kappa-B ligand (RANK/RANKL) pathway, thus inhibiting ...osteoclastogenesis. Since RANK and RANKL are also involved in the immune system activation, denosumab might interfere with the response against infections. Our study aimed to explore the relationship between denosumab treatment and coronavirus disease 2019 (COVID-19).
The occurrence and severity of COVID-19 were recorded in consecutive patients referred to the Endocrinology Department of Papa Giovanni XXIII Hospital, Bergamo, from 1 January 2020 to 1 January 2021. Patients treated with denosumab were compared to outpatient controls. Patients' features were summarized by descriptive statistics. Multivariate logistic regression assessed the relationship between denosumab and COVID-19, adjusting for potential confounders. Subgroup analyses according to age, sex, body mass index (BMI), smoking status, and vitamin D levels were performed.
The final population included 331 patients treated with denosumab and 357 controls. COVID-19 incidence was lower in the denosumab group (7.6% vs. 14.6%, p = 0.004). COVID-19 severity was similar in both groups. Multiple logistic regression confirmed an association between denosumab and a reduced occurrence of symptomatic COVID-19 odds ratio (OR) 0.46, 95% CI 0.21-0.98, p = 0.049. Subgroup analyses suggested a potential protective effect of denosumab in patients over 75 years (OR 0.12, 95% CI 0.02-0.6, p = 0.011), with a significant interaction between denosumab and age categories (p = 0.047).
Our study confirms that denosumab may be safely continued in COVID-19 patients. RANK/RANKL inhibition seems associated with a reduced incidence of symptomatic COVID-19, particularly among the elderly.
The blockade of pro‐inflammatory mediators is a successful approach to improve the engraftment after islet transplantation. L‐aptamers are chemically synthesized, nonimmunogenic bio‐stable ...oligonucleotides that bind and inhibit target molecules conceptually similar to antibodies. We aimed to evaluate if blockade‐aptamer‐based inhibitors of C‐C Motif Chemokine Ligand 2/monocyte chemoattractant protein‐1 (CCL2/MCP‐1) and C‐X‐C Motif Chemokine Ligand 12/stromal cell‐derived factor‐1 (CXCL12/SDF‐1) are able to favor islet survival in mouse models for islet transplantation and for type 1 diabetes. We evaluated the efficacy of the CCL2‐specific mNOX‐E36 and the CXCL12‐specific NOX‐A12 on islet survival in a syngeneic mouse model of intraportal islet transplantation and in a multiple low doses of streptozotocin (MLD‐STZ) diabetes induction model. Moreover, we characterized intrahepatic infiltrated leukocytes by flow cytometry before and 3 days after islet infusion in presence or absence of these inhibitors. The administration for 14 days of mNOX‐E36 and NOX‐A12 significantly improved islet engraftment, either compound alone or in combination. Intrahepatic islet transplantation recruited CD45+ leucocytes and more specifically CD45+/CD11b+ mono/macrophages; mNOX‐E36 and NOX‐A12 treatments significantly decreased the recruitment of inflammatory monocytes, CD11b+/Ly6Chigh/CCR2+ and CD11b+/Ly6Chigh/CXCR4+ cells, respectively. Additionally, both L‐aptamers significantly attenuated diabetes progression in the MLD‐STZ model. In conclusion, CCL2/MCP‐1 and CXCL12/SDF‐1 blockade by L‐aptamers is an efficient strategy to improve islet engraftment and survival.
CCL2/MCP‐1 and CXCL12/SDF‐1 blockade by L‐aptamers is an efficient strategy to improve islet survival in mouse models of islet transplantation and type 1 diabetes.
•Dietary antioxidants (polyphenols and berberine), SIRT1/AMPK and oxidative stress.•Evaluate direct and specific antioxidant activity.•Investigate the effect on SIRT1 expression and AMPK ...activation.•No statistically significant decrease in the number of viable cells was found.
Oxidative stress arises from an imbalance between the production of free radicals and antioxidant defences. Several studies have suggested that dietary antioxidants (such as polyphenols and berberine) may counteract oxidative stress through the involvement of the Sirtuin 1/Adenosine Monophosphate-Activated Protein Kinase (SIRT1/AMPK) pathway. The aim of this study was to evaluate the direct and specific antioxidant activity of some natural compounds, as well as their ability to modulate the expression of SIRT1 and the activation of AMPK.
Quercetin, tyrosol, ferulic acid, catechin, berberine and curcumin were evaluated for their specific and direct antioxidant activity with TOSC assay. Their ability to modulate SIRT1 and AMPK was assessed by immunoblotting assay, while their cytotoxicity by CellTiter-Blue Cell Viability Assay.
No statistically significant decrease (p > 0.05) in the number of viable cells was found upon challenging with the natural compounds. Quercetin exhibited the highest antioxidant activity against peroxyl radical and peroxinitrate derivates, while curcumin showed the best anti-hydroxyl activity with respect to the other compounds and, most importantly, respect to the reference antioxidants. Finally, all the tested compounds significantly increased the SIRT1 expression and the activation of AMPK.
Our results clearly disclose the specific antioxidant activity of these natural compounds and their ability to increase SIRT1 expression and AMPK activation.
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