Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal ...GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feedforward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices from mice we show that upon synchronous optogenetic activation of corticostriatal projections blockade of α4β2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by 'priming' feedforward inhibition, a process that may shape SPN spike timing, striatal processing, and synaptic plasticity.
The T2K fine-grained detectors Amaudruz, P.-A.; Barbi, M.; Bishop, D. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2012, Letnik:
696
Journal Article
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Odprti dostop
T2K is a long-baseline neutrino oscillation experiment searching for νe appearance in a νμ beam. The beam is produced at the J-PARC accelerator complex in Tokai, Japan, and the neutrinos are detected ...by the Super-Kamiokande detector located 295km away in Kamioka. A suite of near detectors (ND280) located 280 m downstream of the production target is used to characterize the components of the beam before they have had a chance to oscillate and to better understand various neutrino interactions on several nuclei. This paper describes the design and construction of two massive fine-grained detectors (FGDs) that serve as active targets in the ND280 tracker. One FGD is composed solely of scintillator bars while the other is partly scintillator and partly water. Each element of the FGDs is described, including the wavelength shifting fiber and Multi-Pixel Photon Counter used to collect the light signals, the readout electronics, and the calibration system. Initial tests and in situ results of the FGDs' performance are also presented.
Supernova detection is a major objective of the Super-Kamiokande (SK) experiment. In the next stage of SK (SK-Gd), gadolinium (Gd) sulfate will be added to the detector, which will improve the ...ability of the detector to identify neutrons. A core-collapse supernova (CCSN) will be preceded by an increasing flux of neutrinos and antineutrinos, from thermal and weak nuclear processes in the star, over a timescale of hours; some of which may be detected at SK-Gd. This could provide an early warning of an imminent CCSN, hours earlier than the detection of the neutrinos from core collapse. Electron antineutrino detection will rely on inverse beta decay events below the usual analysis energy threshold of SK, so Gd loading is vital to reduce backgrounds while maximizing detection efficiency. Assuming normal neutrino mass ordering, more than 200 events could be detected in the final 12 hr before core collapse for a 15-25 solar mass star at around 200 pc, which is representative of the nearest red supergiant to Earth, -Ori (Betelgeuse). At a statistical false alarm rate of 1 per century, detection could be up to 10 hr before core collapse, and a pre-supernova star could be detected by SK-Gd up to 600 pc away. A pre-supernova alert could be provided to the astrophysics community following gadolinium loading.
PURPOSE To investigate whether hormonal receptors and human epidermal growth factor receptor 2 (HER2) change throughout tumor progression, because this may alter patient management. PATIENTS AND ...METHODS The study cohort included female patients with breast cancer in the Stockholm health care region who relapsed from January 1, 1997, to December 31, 2007. Either biochemical or immunohistochemical (IHC)/immunocytochemical (ICC) methods were used to determine estrogen receptor (ER), progesterone receptor (PR), and HER2 status, which was then confirmed by fluorescent in situ hybridization for IHC/ICC 2+ and 3+ status. Results ER (459 patients), PR (430 patients), and HER2 (104 patients) from both primary tumor and relapse were assessed, revealing a change in 32.4% (McNemar's test P < .001), 40.7% (P < .001), and 14.5% (P = .44) of patients, respectively. Assessment of ER (119 patients), PR (116 patients), and HER2 (32 patients) with multiple (from two to six) consecutive relapses showed an alteration in 33.6%, 32.0%, and 15.7% of patients, respectively. A statistically significant differential overall survival related to intraindividual ER and PR status in primary tumor and relapse (log-rank P < .001) was noted. In addition, women with ER-positive primary tumors that changed to ER-negative tumors had a significant 48% increased risk of death (hazard ratio, 1.48; 95% CI, 1.08 to 2.05) compared with women with stable ER-positive tumors. CONCLUSION Patients with breast cancer experience altered hormone receptor and HER2 status throughout tumor progression, possibly influenced by adjuvant therapies, which significantly influences survival. Hence, marker investigations at relapse may potentially improve patient management and survival.
Abstract
Super-Kamiokande has been searching for neutrino bursts characteristic of core-collapse supernovae continuously, in real time, since the start of operations in 1996. The present work focuses ...on detecting more distant supernovae whose event rate may be too small to trigger in real time, but may be identified using an offline approach. The analysis of data collected from 2008 to 2018 found no evidence of distant supernovae bursts. This establishes an upper limit of 0.29 yr
−1
on the rate of core-collapse supernovae out to 100 kpc at 90% C.L. For supernovae that fail to explode and collapse directly to black holes the limit reaches to 300 kpc.
Abstract
The Super-Kamiokande detector can be used to search for neutrinos in time coincidence with gravitational waves detected by the LIGO–Virgo Collaboration (LVC). Both low-energy (7–100 MeV) and ...high-energy (0.1–10
5
GeV) samples were analyzed in order to cover a very wide neutrino spectrum. Follow-ups of 36 (out of 39) gravitational waves reported in the GWTC-2 catalog were examined; no significant excess above the background was observed, with 10 (24) observed neutrinos compared with 4.8 (25.0) expected events in the high-energy (low-energy) samples. A statistical approach was used to compute the significance of potential coincidences. For each observation,
p
-values were estimated using neutrino direction and LVC sky map; the most significant event (GW190602_175927) is associated with a post-trial
p
-value of 7.8% (1.4
σ
). Additionally, flux limits were computed independently for each sample and by combining the samples. The energy emitted as neutrinos by the identified gravitational wave sources was constrained, both for given flavors and for all flavors assuming equipartition between the different flavors, independently for each trigger and by combining sources of the same nature.
Abstract
A new event reconstruction algorithm based on a maximum likelihood method has been developed for Super-Kamiokande. Its improved kinematic and particle identification capabilities enable the ...analysis of atmospheric neutrino data in a detector volume 32% larger than previous analyses and increase the sensitivity to the neutrino mass hierarchy. Analysis of a 253.9 kton$\cdot$year exposure of the Super-Kamiokande IV atmospheric neutrino data has yielded a weak preference for the normal hierarchy, disfavoring the inverted hierarchy at 74% assuming oscillations at the best fit of the analysis.
Saturated fatty acid (SFA) vs polyunsaturated fatty acid (PUFA) may promote nonalcoholic fatty liver disease by yet unclear mechanisms.
To investigate if overeating SFA- and PUFA-enriched diets lead ...to differential liver fat accumulation in overweight and obese humans.
Double-blind randomized trial (LIPOGAIN-2). Overfeeding SFA vs PUFA for 8 weeks, followed by 4 weeks of caloric restriction.
General community.
Men and women who are overweight or have obesity (n = 61).
Muffins, high in either palm (SFA) or sunflower oil (PUFA), were added to the habitual diet.
Lean tissue mass (not reported here). Secondary and exploratory outcomes included liver and ectopic fat depots.
By design, body weight gain was similar in SFA (2.31 ± 1.38 kg) and PUFA (2.01 ± 1.90 kg) groups, P = 0.50. SFA markedly induced liver fat content (50% relative increase) along with liver enzymes and atherogenic serum lipids. In contrast, despite similar weight gain, PUFA did not increase liver fat or liver enzymes or cause any adverse effects on blood lipids. SFA had no differential effect on the accumulation of visceral fat, pancreas fat, or total body fat compared with PUFA. SFA consistently increased, whereas PUFA reduced circulating ceramides, changes that were moderately associated with liver fat changes and proposed markers of hepatic lipogenesis. The adverse metabolic effects of SFA were reversed by calorie restriction.
SFA markedly induces liver fat and serum ceramides, whereas dietary PUFA prevents liver fat accumulation and reduces ceramides and hyperlipidemia during excess energy intake and weight gain in overweight individuals.
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