A
bstract
We study the scattering of massless probes in the vicinity of the
photon-sphere
of asymptotically AdS black holes and horizon-free microstate geometries (fuzzballs). We find that these ...exhibit a chaotic behaviour characterised by exponentially large deviations of nearby trajectories. We compute the Lyapunov exponent λ governing the exponential growth in
d
dimensions and show that it is bounded from above by
λ
b
=
d
−
3
/
2
b
min
where
b
min
is the minimal impact parameter under which a massless particle is swallowed by the black hole or gets trapped in the fuzzball for a very long time. Moreover we observe that λ is typically below the advocated bound on chaos λ
H
= 2
πκ
B
T
∕ ħ, that in turn characterises the radial fall into the horizon, but the bound is violated in a narrow window near extremality, where the photon-sphere coalesces with the horizon. Finally, we find that fuzzballs are characterised by Lyapunov exponents smaller than those of the corresponding BH’s suggesting the possibility of discriminating the existence of micro-structures at horizon scales via the detection of ring-down modes with time scales λ
−
1
longer than those expected for a BH of the given mass and spin.
The dark side of fuzzball geometries Bianchi, M.; Consoli, D.; Grillo, A. ...
The journal of high energy physics,
05/2019, Letnik:
2019, Številka:
5
Journal Article
Recenzirano
Odprti dostop
A
bstract
Black holes absorb any particle impinging with an impact parameter below a critical value. We show that 2- and 3-charge fuzzball geometries exhibit a similar trapping behaviour for a ...selected choice of the impact parameter of incoming massless particles. This suggests that the blackness property of black holes arises as a collective effect whereby each micro-state absorbs a specific channel.
Research in animals and humans has shown that type 2 diabetes and its prodromal state, insulin resistance, promote major pathological hallmarks of Alzheimer's disease (AD), such as the formation of ...amyloid plaques and neurofibrillary tangles (NFT). Worrisomely, dysregulated amyloid beta (Aβ) metabolism has also been shown to promote central nervous system insulin resistance; although the role of tau metabolism remains controversial. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted insulin signaling. They also provide strong support for the hypothesis that pharmacologically restoring brain insulin signaling could represent a promising strategy to curb the development and progression of AD. In this context, great hopes have been attached to the use of intranasal insulin. This drug delivery method increases cerebrospinal fluid concentrations of insulin in the absence of peripheral side effects, such as hypoglycemia. With this in mind, the present review will also summarize current knowledge on the efficacy of intranasal insulin to mitigate major pathological symptoms of AD, i.e., cognitive impairment and deregulation of Aβ and tau metabolism.
Light rings of five-dimensional geometries Bianchi, M.; Consoli, D.; Grillo, A. ...
The journal of high energy physics,
03/2021, Letnik:
2021, Številka:
3
Journal Article
Recenzirano
Odprti dostop
A
bstract
We study massless geodesics near the photon-spheres of a large family of solutions of Einstein-Maxwell theory in five dimensions, including BHs, naked singularities and smooth horizon-less ...JMaRT geometries obtained as six-dimensional uplifts of the five-dimensional solution. We find that a light ring of unstable photon orbits surrounding the mass center is always present, independently of the existence of a horizon or singularity. We compute the Lyapunov exponent, characterizing the chaotic behaviour of geodesics near the ‘photon-sphere’ and the time decay of ring-down modes dominating the response of the geometry to perturbations at late times. We show that, for geometries free of naked singularities, the Lyapunov exponent is always bounded by its value for a Schwarzschild BH of the same mass.
Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ ...dysfunction, age, genetics) and extrinsic (e.g., drug–drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision‐making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.
Clinical Pharmacology & Therapeutics (2011) 89 2, 259–267. doi:10.1038/clpt.2010.298
Understanding the genetic and environmental factors that structure plant microbiomes is necessary for leveraging these interactions to address critical needs in agriculture, conservation, and ...sustainability. Legumes, which form root nodule symbioses with nitrogen-fixing rhizobia, have served as model plants for understanding the genetics and evolution of beneficial plant-microbe interactions for decades, and thus have added value as models of plant-microbiome interactions. Here we use a common garden experiment with 16S rRNA gene amplicon and shotgun metagenomic sequencing to study the drivers of microbiome diversity and composition in three genotypes of the model legume Medicago truncatula grown in two native soil communities.
Bacterial diversity decreased between external (rhizosphere) and internal plant compartments (root endosphere, nodule endosphere, and leaf endosphere). Community composition was shaped by strong compartment × soil origin and compartment × plant genotype interactions, driven by significant soil origin effects in the rhizosphere and significant plant genotype effects in the root endosphere. Nevertheless, all compartments were dominated by Ensifer, the genus of rhizobia that forms root nodule symbiosis with M. truncatula, and additional shotgun metagenomic sequencing suggests that the nodulating Ensifer were not genetically distinguishable from those elsewhere in the plant. We also identify a handful of OTUs that are common in nodule tissues, which are likely colonized from the root endosphere.
Our results demonstrate strong host filtering effects, with rhizospheres driven by soil origin and internal plant compartments driven by host genetics, and identify several key nodule-inhabiting taxa that coexist with rhizobia in the native range. Our results set the stage for future functional genetic experiments aimed at expanding our pairwise understanding of legume-rhizobium symbiosis toward a more mechanistic understanding of plant microbiomes. Video Abstract.
Abstract In the central nervous system (CNS) insulin mediates a variety of effects including feeding, metabolism and cognition. The cognitive enhancing effects of insulin are proposed to be mediated ...through activation of insulin receptors in the hippocampus, an important integration center for learning and memory in the mammalian brain. Since less is known regarding insulin signaling events in the hippocampus, the aim of the current study was to determine whether insulin stimulates similar signaling cascades and GLUT4 translocation in the rat hippocampus as has been described in peripheral tissues. Intracerebroventricular administration of insulin increases hippocampal insulin levels and also stimulates the phosphorylation of Akt in a time-dependent manner. Insulin also stimulates the translocation of GLUT4 to hippocampal plasma membranes in a time course that mirrors the increases in glucose uptake observed during the performance of hippocampal-dependent tasks. Insulin stimulated phosphorylation of Akt and translocation of GLUT4 were blocked by pretreatment with the PI3-kinase inhibitor LY294002. Confocal immunofluorescence determined that insulin stimulated phosphorylation of Akt was localized to neurons and colocalized with the insulin receptor and GLUT4 in the rat hippocampus, thereby identifying the functional anatomical substrates of insulin signaling in the hippocampus. These results demonstrate that insulin-stimulated translocation of GLUT4 to the plasma membrane in the rat hippocampus occurs via similar mechanisms as described in peripheral tissues and suggests that insulin-mediated translocation of GLUT4 may provide a mechanism through which hippocampal neurons rapidly increase glucose utilization during increases in neuronal activity associated with hippocampal-dependent learning.
Advanced glycation end-products (AGEs) are formed from the so-called Amadori products by rearrangement followed by other reactions giving rise to compounds bound irreversibly. The structure of some ...of them is shown and the mechanism of formation is described. Several AGE binding molecules (Receptors for AGE, RAGE) are known and it is thought that many of the effects caused by AGEs are mediated by RAGE. Some of these were shown to be toxic, and called TAGE. The mechanism of detoxification of glyoxal and methylglyoxal by the glyoxalase system is described and also the possibility to eliminate glycated proteins by deglycation enzymes. Compounds able to inhibit AGEs formation are also taken into consideration.
In the periphery insulin plays a critical role in the regulation of metabolic homeostasis by stimulating glucose uptake into peripheral organs. In the central nervous system (CNS), insulin plays a ...critical role in the formation of neural circuits and synaptic connections from the earliest stages of development and facilitates and promotes neuroplasticity in the adult brain. Beyond these physiological roles of insulin, a shared feature between the periphery and CNS is that decreases in insulin receptor activity and signaling (i.e. insulin resistance) contributes to the pathological consequences of type 2 diabetes (T2DM) and obesity. Indeed, clinical and preclinical studies illustrate that CNS insulin resistance elicits neuroplasticity deficits that lead to decreases in cognitive function and increased risk of neuropsychiatric disorders. The goals of this review are to provide an overview of the literature that have identified the neuroplasticity deficits observed in T2DM and obesity, as well as to discuss the potential causes and consequences of insulin resistance in the CNS, with a particular focus on how insulin resistance impacts hippocampal neuroplasticity. Interestingly, studies that have examined the effects of hippocampal-specific insulin resistance illustrate that brain insulin resistance may impair neuroplasticity independent of peripheral insulin resistance, thereby supporting the concept that restoration of brain insulin activity is an attractive therapeutic strategy to ameliorate or reverse cognitive decline observed in patients with CNS insulin resistance such as T2DM and Alzheimer's Disease.
•Insulin resistance is a core pathology feature of metabolic disorders and Alzheimer's•Peripheral and CNS insulin resistance elicit neuroplasticity deficits•Hippocampal-specific insulin resistance impairs synaptic plasticity and cognition•Restoration of brain insulin activity is an emerging strategy for cognitive deficits
Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system, including the hippocampus. To elucidate the functional role of hippocampal IRs independent of ...metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (LV-IRAS). LV-IRAS effectively downregulates IR expression in the rat hippocampus without affecting body weight, adiposity, or peripheral glucose homeostasis. Nevertheless, hippocampal neuroplasticity was impaired in LV-IRAS-treated rats. High-frequency stimulation, which evoked robust long-term potentiation (LTP) in brain slices from LV control rats, failed to evoke LTP in LV-IRAS-treated rats. GluN2B subunit levels, as well as the basal level of phosphorylation of GluA1, were reduced in the hippocampus of LV-IRAS rats. Moreover, these deficits in synaptic transmission were associated with impairments in spatial learning. We suggest that alterations in the expression and phosphorylation of glutamate receptor subunits underlie the alterations in LTP and that these changes are responsible for the impairment in hippocampal-dependent learning. Importantly, these learning deficits are strikingly similar to the impairments in complex task performance observed in patients with diabetes, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of cognitive deficits independent of glycemic control.
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