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.
Calsenilin is a calcium ion (Ca
2+
)-binding protein involved in regulating the intracellular concentration of Ca
2+
, a second messenger that controls multiple cellular signaling pathways. The ...ryanodine receptor (RyR) amplifies Ca
2+
signals entering the cytoplasm by releasing Ca
2+
from endoplasmic reticulum (ER) stores, a process termed calcium-induced calcium release (CICR). Here, we describe a novel mechanism, in which calsenilin controls the activity of neuronal RyRs. We show calsenilin co-localized with RyR2 and 3 in the ER of mouse hippocampal and cortical neurons using immunocytochemistry. The underlying protein-protein interaction between calsenilin and the RyR was determined in mouse central nervous system (CNS) neurons using immunoprecipitation studies. The functional relevance of this interaction was assayed with single-channel electrophysiology. At low physiological Ca
2+
concentrations, calsenilin binding to the cytoplasmic face of neuronal RyRs decreased the RyR’s open probability, while calsenilin increased the open probability at high physiological Ca
2+
concentrations. This novel molecular mechanism was studied further at the cellular level, where faster release kinetics of caffeine-induced Ca
2+
release were measured in SH-SY5Y neuroblastoma cells overexpressing calsenilin. The interaction between calsenilin and neuronal RyRs reveals a new regulatory mechanism and possibly a novel pharmacological target for the control of Ca
2+
release from intracellular stores.
Abstract
The non-thermal nature of self-propelling colloids offers new insights into non-equilibrium physics. The central mathematical model to describe their trajectories is active Brownian motion, ...where a particle moves with a constant speed, while randomly changing direction due to rotational diffusion. While several feedback strategies exist to achieve position-dependent velocity, the possibility of spatial and temporal control over rotational diffusion, which is inherently dictated by thermal fluctuations, remains untapped. Here, we decouple rotational diffusion from thermal fluctuations. Using external magnetic fields and discrete-time feedback loops, we tune the rotational diffusivity of active colloids above and below its thermal value at will and explore a rich range of phenomena including anomalous diffusion, directed transport, and localization. These findings add a new dimension to the control of active matter, with implications for a broad range of disciplines, from optimal transport to smart materials.
Dysregulated pH is a common characteristic of cancer cells, as they have an increased intracellular pH (pH
) and a decreased extracellular pH (pH
) compared with normal cells. Recent work has ...expanded our knowledge of how dysregulated pH dynamics influences cancer cell behaviors, including proliferation, metastasis, metabolic adaptation and tumorigenesis. Emerging data suggest that the dysregulated pH of cancers enables these specific cell behaviors by altering the structure and function of selective pH-sensitive proteins, termed pH sensors. Recent findings also show that, by blocking pH
increases, cancer cell behaviors can be attenuated. This suggests ion transporter inhibition as an effective therapeutic approach, either singly or in combination with targeted therapies. In this Cell Science at a Glance article and accompanying poster, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression and adaptation.
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
ASICs for LHC intermediate tracking detectors Hall, G.; Grillo, A.A.
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
20/May , Letnik:
1050
Journal Article
Recenzirano
Odprti dostop
The tracking detectors proposed for the LHC were unprecedented in their size and operational requirements, especially radiation tolerance and data rates. When they were first envisaged it was ...uncertain that technologies would be available which would meet the specifications, and considerable R&D was necessary to demonstrate this. In particular, customised electronic integrated circuits were evidently essential, yet they were probably technologically the least certain components. The radiation levels and the readout rates in earlier generations of collider experiments were far below those required for the LHC trackers and the number of LHC readout chips required was much larger. Nevertheless, solutions were eventually found, which continue to function reliably with excellent performance. In many ways, the tracker ASIC developments laid foundations and blazed trails for chips later designed for many other sub-detector systems.
The ATLAS and CMS trackers developed different solutions to the LHC challenges, and are representative of other LHC systems. This review focuses on the ASIC developments undertaken by these two experiments to explain the most important innovations, recent progress and future challenges.
The term “intermediate tracking detectors” is meant to differentiate from the innermost trackers close to the beam pipe and interaction region. This region is served by pixel detectors, whose development began later than the LHC trackers discussed here.
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.
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.
Abstract
The GLASS-JWST Early Release Science (hereafter GLASS-JWST-ERS) Program will obtain and make publicly available the deepest extragalactic data of the ERS campaign. It is primarily designed ...to address two key science questions, namely, “what sources ionized the universe and when?” and “how do baryons cycle through galaxies?”, while also enabling a broad variety of first look scientific investigations. In primary mode, it will obtain NIRISS and NIRSpec spectroscopy of galaxies lensed by the foreground Hubble Frontier Field cluster, Abell 2744. In parallel, it will use NIRCam to observe two fields that are offset from the cluster center, where lensing magnification is negligible, and which can thus be effectively considered blank fields. In order to prepare the community for access to this unprecedented data, we describe the scientific rationale, the survey design (including target selection and observational setups), and present pre-commissioning estimates of the expected sensitivity. In addition, we describe the planned public releases of high-level data products, for use by the wider astronomical community.
Abstract
Through the process of domestication, selection is targeted on a limited number of plant traits that are typically associated with yield. As an unintended consequence, domesticated plants ...often perform poorly compared to their wild progenitors for a multitude of traits that were not under selection during domestication, including abiotic and biotic stress tolerance. Over the past decade, advances in sequencing technology have allowed for the rigorous characterization of host-associated microbial communities, termed the microbiome. It is now clear that nearly every conceivable plant interaction with the environment is mediated by interactions with the microbiome. For this reason, plant–microbiome interactions are an area of great promise for plant breeding and crop improvement. Here, we review the literature to assess the potential impact that domestication has had on plant–microbiome interactions and the current understanding of the genetic basis of microbiome variation to inform plant breeding efforts. Overall, we find limited evidence that domestication impacts the diversity of microbiomes, but domestication is often associated with shifts in the abundance and composition of microbial communities, including taxa of known functional significance. Moreover, genome-wide association studies and mutant analysis have not revealed a consistent set of core candidate genes or genetic pathways that confer variation in microbiomes across systems. However, such studies do implicate a consistent role for plant immunity, root traits, root and leaf exudates and cell wall integrity as key traits that control microbiome colonization and assembly. Therefore, selection on these key traits may pose the most immediate promise for enhancing plant–microbiome interactions through breeding.
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