Critical postsynaptic density 95/disc large/zonula occludens-1 interactions by glutamate receptor 1 (GluR1) and GluR2 required at different subcellular sites

Interactions between AMPA receptor subunits and proteins containing postsynaptic density 95/disc large/zonula occludens-1 (PDZ) domains have been shown to play critical roles in the proper trafficking of receptors to excitatory synapses. Synaptic accumulation of AMPA receptors containing the glutamate receptor 1 (GluR1) subunit can be driven by calcium/calmodulin-dependent protein kinase II activity or long-term potentiation and requires an interaction between GluR1 and a type I PDZ domain-containing protein. Synaptic incorporation of AMPA receptors with only GluR2 occurs continuously, and this requires an interaction between GluR2 and a type II PDZ domain-containing protein. We used dual-channel, two-photon laser scanning microscopy to provide high-resolution visualization and quantification of green fluorescent protein-tagged AMPA receptors in different subcellular compartments. We showed that mutations on GluR1 or GluR2 AMPA subunit that perturb interactions with PDZ domain proteins lead to the accumulation of these receptors at different subcellular sites. GluR1 mutants accumulate in the dendrite, whereas GluR2 mutants accumulate in dendritic spines. This suggests that the critical PDZ domain interactions are required for entry into spines for GluR1 and for entry into synapses for GluR2

The influence of light attenuation on the biogeomorphology of a marine karst cave: a case study of Puerto Princesa Underground River, Palawan, the Philippines

Karst caves are unique biogeomorphological systems. Cave walls offer habitat for microorganisms which in-turn have a geomorphological role via their involvement in rock weathering, erosion and mineralisation. The attenuation of light with distance into caves is known to affect ecology, but the implications of this for biogeomorphological processes and forms have seldom been examined. Here we describe a semi-quantitative microscopy study comparing the extent, structure, and thickness of biocover and depth of endolithic penetration for samples of rock from the Puerto Princesa Underground River system in Palawan, the Philippines, which is a natural UNESCO World Heritage Site. Organic growth at the entrance of the cave was abundant (100% occurrence) and complex, dominated by phototrophic organisms (green microalgae, diatoms, cyanobacteria, mosses and lichens). Thickness of this layer was 0.28 ± 0.18 mm with active endolith penetration into the limestone (mean depth = 0.13 ± 0.03 mm). In contrast, phototrophs were rare 50 m into the cave and biofilm cover was significantly thinner (0.01 ± 0.01 mm, p < 0.000) and spatially patchy (33% occurrence). Endolithic penetration here was also shallower (< 0.01 mm, p < 0.000) and non-uniform. Biofilm was found 250 m into the cave, but with a complete absence of phototrophs and no evidence of endolithic bioerosion. We attribute these findings to light-induced stress gradients, showing that the influence of light on phototroph abundance has knock-on consequences for the development of limestone morphological features. In marine caves this includes notches, which were most well-developed at the sheltered cave entrance of our study site, and for which variability in formation rates between locations is currently poorly understood

Fat-free noncontrast whole-heart CMR with fast and power-optimized off-resonant water excitation pulses

Background: Cardiovascular MRI (CMR) faces challenges due to the interference of bright fat signals in visualizing anatomical structures. Effective fat suppression is crucial when using whole-heart CMR. Conventional methods often fall short due to rapid fat signal recovery and water-selective off-resonant pulses come with tradeoffs between scan time and RF energy deposit. A lipid-insensitive binomial off-resonant (LIBOR) RF pulse is introduced, addressing concerns about RF energy and scan time for CMR at 3T. Methods: A short LIBOR pulse was developed and implemented in a free-breathing respiratory self-navigated whole-heart sequence at 3T. A BORR pulse with matched duration, as well as previously used LIBRE pulses, were implemented and optimized for fat suppression in numerical simulations and validated in healthy subjects (n=3). Whole-heart CMR was performed in healthy subjects (n=5) with all four pulses. The SNR of ventricular blood, skeletal muscle, myocardium, and subcutaneous fat, and the coronary vessel sharpness and length were compared. Results: Experiments validated numerical findings and near homogeneous fat suppression was achieved with all pulses. Comparing the short pulses (1ms), LIBOR reduced the RF power two-fold compared with LIBRE, and three-fold compared with BORR, and LIBOR significantly decreased overall fat SNR. The reduction in RF duration shortened the whole-heart acquisition from 8.5min to 7min. No significant differences in coronary arteries detection and sharpness were found when comparing all four pulses. Conclusion: LIBOR enabled whole-heart CMR under 7 minutes at 3T, with large volume fat signal suppression, while reducing RF power compared with LIBRE and BORR. LIBOR is an excellent candidate to address SAR problems encountered in CMR where fat suppression remains challenging and short RF pulses are required.Comment: 25 pages, 7 figures, 2 table

Parkinson’s disease dyskinesias possibly relate to greater dopamine transporter losses in the putamen over time

The pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease is incompletely understood. This study was designed to investigate in Parkinson’s patients, whether time-related changes in striatal dopamine transporter availability are associated to the appearance of dyskinesias. 15 Parkinson’s patients had dopamine transporter-specific SPECT imaging with 123I-FP-CIT twice: at baseline (when they were drug naïve) and at follow-up (6.31±2.29 years from baseline), and were followed up clinically every six months. At the end of the study, patients were divided in two groups according to whether they had developed dyskinesias or not. Semi-quantification of 123I-FP-CIT data was performed using the occipital cortex as the reference region. Specific binding ratios were calculated for the putamen and the caudate. During the clinical follow-up, all Parkinson’s patients were treated pharmaceutically. 8 patients developed dyskinesias, while 7 remained nondyskinetic. At baseline, the two groups had similar 123I-FP-CIT specific binding ratio values for the putamen and the caudate (p>0.05). Also, between-group differences in age, disease duration, and Hoehn & Yahr scores were not statistically significant. Over-time, the putaminal 123I-FP-CIT specific binding ratio values in the dyskinetic group decreased significantly (p<0.01). The nondyskinetic patients had smaller reductions (p<0.05) during the same period of time. At follow-up, the dyskinetic patients had significantly higher Hoehn & Yahr scores (p<0.01) and were taking higher levodopa equivalent doses (p<0.001), as compared to the nondyskinetic patients. The development of Parkinson’s dyskinesias is related to a faster progression rate, as reflected by marked putaminal dopamine transporter decreases

Confinement effects and acid strength in zeolites

Chemical reactivity and sorption in zeolites are coupled to confinement and—to a lesser extent—to the acid strength of Brønsted acid sites (BAS). In presence of water the zeolite Brønsted acid sites eventually convert into hydronium ions. The gradual transition from zeolite Brønsted acid sites to hydronium ions in zeolites of varying pore size is examined by ab initio molecular dynamics combined with enhanced sampling based on Well-Tempered Metadynamics and a recently developed set of collective variables. While at low water content (1–2 water/BAS) the acidic protons prefer to be shared between zeolites and water, higher water contents (n &gt; 2) invariably lead to solvation of the protons within a localized water cluster adjacent to the BAS. At low water loadings the standard free energy of the formed complexes is dominated by enthalpy and is associated with the acid strength of the BAS and the space around the site. Conversely, the entropy increases linearly with the concentration of waters in the pores, favors proton solvation and is independent of the pore size/shape