Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour ...and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Many tumors become addicted to autophagy for survival, suggesting inhibition of autophagy as a potential broadly applicable cancer therapy. ULK1/Atg1 is the only serine/threonine kinase in the core ...autophagy pathway and thus represents an excellent drug target. Despite recent advances in the understanding of ULK1 activation by nutrient deprivation, how ULK1 promotes autophagy remains poorly understood. Here, we screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. SBI-0206965 greatly synergized with mechanistic target of rapamycin (mTOR) inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic.
Display omitted
•ULK1 phosphorylates multiple autophagy components, including VPS34 on Ser249•SBI-0206965 is a highly selective ULK1 kinase inhibitor that blocks autophagy•SBI-0206965 combined with starvation or mTOR inhibition leads to ULK1 degradation•SBI-0206965 synergizes with mTOR inhibition to induce cell death
ULK1 is a serine/threonine kinase that initiates autophagy in response to nutrient deprivation. Egan et al. define ULK1’s consensus phosphorylation motif, demonstrate that ULK1 phosphorylates several autophagy components, and develop a ULK1 small molecule inhibitor (SBI-0206965). SBI-0206965 synergizes with mTOR inhibition to enhance apoptosis in tumor cells, suggesting therapeutic opportunities.
Thermal aging of the high-temperature shape memory alloy 50.3Ni–29.7Ti–20Hf (at.%) introduces a novel precipitate phase that plays an important role in improving shape memory properties. The ...precipitate phase was investigated by conventional electron diffraction, high-resolution scanning transmission electron microscopy (STEM) and three-dimensional atom probe tomography. An unrelaxed orthorhombic atomic structural model is proposed based on these observations. This model was subsequently relaxed by ab initio calculations. As a result of the relaxation, atom shuffle displacements occur, which in turn yields improved agreement with the STEM images. The relaxed structure, which is termed the “H phase”, has also been verified to be thermodynamically stable at 0K.
Drug-induced cardiotoxicity arises primarily when a compound alters the electrophysiological properties of cardiomyocytes. Features of intracellular action potentials (iAPs) are powerful biomarkers ...that predict proarrhythmic risks. In the last decade, a number of vertical nanoelectrodes have been demonstrated to achieve parallel and minimally-invasive iAP recordings. However, the large variability in success rate and signal strength have hindered nanoelectrodes from being broadly adopted for proarrhythmia drug assessment. In this work, we develop vertically-aligned nanocrown electrodes that are mechanically robust and achieve > 99% success rates in obtaining intracellular access through electroporation. We validate the accuracy of nanocrown electrode recordings by simultaneous patch clamp recording from the same cell. Finally, we demonstrate that nanocrown electrodes enable prolonged iAP recording for continual monitoring of the same cells upon the sequential addition of four incremental drug doses. Our technology development provides an advancement towards establishing an iAP screening assay for preclinical evaluation of drug-induced arrhythmogenicity.
Abstract
Colloidal liquid crystals are an emerging class of soft materials that naturally combine the unique properties of both liquid crystal molecules and colloidal particles. Chiral liquid crystal ...blue phases are attractive for use in fast optical displays and electrooptical devices, but the construction of blue phases is limited to a few chiral building blocks and the formation of blue phases from achiral ones is often counterintuitive. Herein we demonstrate that achiral dumbbell-shaped colloids can assemble into a rich variety of characteristic liquid crystal phases, including nematic phases with lock structures, smectic phase, and particularly experimental observation of blue phase III with double-twisted chiral columns. Phase diagrams from experiments and simulations show that the existence and stable regions of different liquid crystal phases are strongly dependent on the geometrical parameters of dumbbell-shaped colloids. This work paves a new route to the design and construction of blue phases for photonic applications.
A
bstract
Using 10
.
1
×
10
9
J/ψ
events produced by the Beijing Electron Positron Collider (BEPCII) at a center-of-mass energy
s
= 3
.
097 GeV and collected with the BESIII detector, we present a ...search for the rare semi-leptonic decay
J/ψ → D
−
e
+
ν
e
+ c.c. No excess of signal above background is observed, and an upper limit on the branching fraction ℬ(
J
/
ψ
→
D
−
e
+
ν
e
+
c
.
c
.) < 7.1 × 10
−8
is obtained at 90% confidence level. This is an improvement of more than two orders of magnitude over the previous best limit.
How environmental and physiological signals interact to influence neural circuits underlying developmentally programmed social interactions such as male territorial aggression is poorly understood. ...We have tested the influence of sensory cues, social context, and sex hormones on progesterone receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) that are critical for male territorial aggression. We find that these neurons can drive aggressive displays in solitary males independent of pheromonal input, gonadal hormones, opponents, or social context. By contrast, these neurons cannot elicit aggression in socially housed males that intrude in another male’s territory unless their pheromone-sensing is disabled. This modulation of aggression cannot be accounted for by linear integration of environmental and physiological signals. Together, our studies suggest that fundamentally non-linear computations enable social context to exert a dominant influence on developmentally hard-wired hypothalamus-mediated male territorial aggression.
•PR+ VMHvl neurons can drive aggression in singly housed, resident male mice•This aggression can occur absent chemosensing, gonadal hormones, or opponents•PR+ VMHvl neurons do not trigger aggression in socially housed intruder males•Disabling chemosensing enables PR+ VMHvl-triggered aggression in these males
Yang et al. show that PR+ VMHvl neurons trigger aggression in solitary male mice independent of pheromone-sensing, gonadal hormones, opponents, or social context. By contrast, these neurons can trigger aggression in socially housed intruder males when their pheromone sensing is disabled.
A novel data-model-fusion prognostic framework is developed in this paper to improve the accuracy of system state long-horizon forecasting. This framework strategically integrates the strengths of ...the data-driven prognostic method and the model-based particle filtering approach in system state prediction while alleviating their limitations. In the proposed methodology, particle filtering is applied for system state estimation in parallel with parameter identification of the prediction model (with unknown parameters) based on Bayesian learning. Simultaneously, a data-driven predictor is employed to learn the system degradation pattern from history data so as to predict system evolution (or future measurements). An innovative feature of the proposed fusion prognostic framework is that the predicted measurements (with uncertainties) from the data-driven predictor will be properly managed and utilized by the particle filtering to further update the prediction model parameters, thereby enabling markedly better prognosis as well as improved forecasting transparency. As an application example, the developed fusion prognostic framework is employed to predict the remaining useful life of lithium ion batteries through electrochemical impedance spectroscopy tests. The investigation results demonstrate that the proposed fusion prognostic framework is an effective forecasting tool that can integrate the strengths of both the data-driven method and the particle filtering approach to achieve more accurate state forecasting.
In this trial, 3445 patients with heart failure and a preserved ejection fraction were assigned to spironolactone or placebo. At a mean of 3.3 years, there was no significant difference in death from ...cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure.
Many patients with heart failure have a normal or near-normal left ventricular ejection fraction.
1
–
4
Such patients share common signs and symptoms, as well as an impaired quality of life and a poor prognosis, with patients who have heart failure and a reduced ejection fraction.
5
–
8
However, the benefit of most medical therapies for heart failure is limited to those with a reduced ejection fraction, generally 40% or less.
1
,
2
,
9
The lack of favorable evidence from clinical-outcome trials involving patients with heart failure and a preserved left ventricular ejection fraction is reflected in current guidelines, which offer no specific . . .
PDF
