Notes

Ozanimod: The First-in-Class Sphingosine 1-Phosphate Receptor Modulator to treat Ulcerative Colitis.
Visual working memory is the ability to hold visual information temporarily in mind. A key feature of working memory is its starkly limited capacity, such that only a few simple items can be remembered at once. Prior work has shown that this capacity limit cannot be circumvented by providing additional encoding time, whether providing just 200 ms or up to 1300 ms, capacity is still limited to only three to four items. In contrast, Brady et al. (2016) hypothesized that real-world objects, but not simple items used in prior research, benefit from additional encoding time and are not subject to traditional capacity limits. They supported this hypothesis with results from both behavior and the contralateral delay activity (CDA), an EEG marker of working memory storage, and concluded that familiar, complex stimuli are necessary to observe encoding time effects. Here, we conducted three replications of Brady et al.'s key manipulation with a larger number of human participants and more trials per condition. We failed to replicate their primary behavioral result (objects benefit more than colors from additional encoding time) and failed to observe an object-specific increase in the CDA. Instead, we found that encoding time benefitted both simple color items and real-world objects, in contrast to both the findings by Brady et al., and some prior work on this topic. BLU9931 Overall, we observed no support for the hypothesis that real-world objects have a different capacity than colored squares. We discuss the implications of our findings for theories of visual working memory (VWM).Sheddases are specialized proteases that control the abundance and function of membrane proteins by cleaving their substrate's extracellular domain (ectodomain), a process known as shedding. Hundreds of shedding substrates have been identified, but little is known about the mechanisms that govern ectodomain shedding. Iwagishi et al. now report that negatively charged amino acids in the membrane-proximal juxtamembrane domain of substrates make them resistant to shedding by the metalloprotease ADAM17. These findings will help researchers better understand the regulation of shedding and may aid in the development of drugs targeting sheddases.
To assess whether cardiorespiratory fitness (CRF) and handgrip strength, two objective markers of physical fitness, are associated with age-related macular degeneration (AMD).

We analysed cross-sectional data from the population-based Study of Health in Pomerania (2008-2012) including 1173 adult men and women aged 20-79years. Fundus photography of the central retina was recorded with a non-mydriatic camera, and images were graded according to an established clinical AMD classification scale by an experienced reader. CRF was measured using peak oxygen uptake (peakVO
), oxygen uptake at the anaerobic threshold (VO
@AT), and maximum power output (W
) from standardised cardiopulmonary exercise testing on a bicycle ergometer according to a modified Jones protocol. Handgrip strength was assessed using a handheld dynamometer. Adjusted prevalence ratios (PR) for the associations of peakVO
, VO
@AT, W
and handgrip strength with AMD were derived from multivariable Poisson regression models.

PeakVO
, VO
@AT, W
and handgrip strength were not associated with AMD. Adjusted PR for AMD associated with a 1-SD increment in peakVO
, VO
@AT, W
and handgrip strength were 1.05 (95% CI 0.82 to 1.34), 0.96 (95% CI 0.78 to 1.18), 1.10 (95% CI 0.86 to 1.41) and 1.01 (95% CI 0.79 to 1.30), respectively. These associations were not modified by age, sex, smoking, body mass index and diabetes. Estimates in sensitivity analysis for confounding, selection bias and missing data were similar.

In our study, CRF and handgrip strength were not associated with AMD. Nevertheless, longitudinal studies with bigger sample sizes are needed to furtherly examine these associations.
In our study, CRF and handgrip strength were not associated with AMD. Nevertheless, longitudinal studies with bigger sample sizes are needed to furtherly examine these associations.
To evaluate and report the outcomes following phacoemulsification on four eyes, 45years or more after corneal transplantation.

A retrospective case series of four eyes in three patients (P1, P2, P3), undergoing phacoemulsification at least 45years after corneal transplantation by Dr Ramon Castroviejo. Corneal graft survival outcome measures included central corneal thickness (CCT), best-corrected visual acuity (BCVA), corneal clarity and endothelial cell count (ECC).

Phacoemulsification was successfully completed in all four cases with no instances of graft failure during the postoperative follow-up period, which ranged from 17 months to 76months. At the conclusion of the follow-up period, all four grafts remained clear, and BCVA remained better than or similar to preoperative values. Long-term follow-up revealed no meaningful changes in CCT after phacoemulsification. All but one case experienced a decrease in ECC, with ECC values in the four cases ranging from 538 cells/mm
to 1436 cells/mm
at the conclusion of postoperative follow-up.

Limited data have been published on the long-term survival of corneal grafts after intraocular surgery, especially for extremely 'mature' corneal transplants. This case series demonstrates that with appropriate preoperative, intraoperative and postoperative measures, successful phacoemulsification can be performed in these cases with excellent long-term results.
Limited data have been published on the long-term survival of corneal grafts after intraocular surgery, especially for extremely 'mature' corneal transplants. This case series demonstrates that with appropriate preoperative, intraoperative and postoperative measures, successful phacoemulsification can be performed in these cases with excellent long-term results.
To investigate the prevalence and predictors of pseudomyopia in Chinese children and its association with myopia progression.

A prospective, school-based, cohort study of 6- and 13-year-old children was conducted in Anyang, China. Pre-cycloplegic and post-cycloplegic autorefraction were performed at baseline and 1 year later. Pseudomyopia was defined as spherical equivalent refractive (SER) error in the better-seeing eye ≤-0.50 D before cycloplegia and >-0.50 D after cycloplegia. Among pseudomyopic children, pseudomyopic power was defined as non-cycloplegic SER subtracted from cycloplegic SER. Market survey was collected in all optometry stores in Anyang city to investigate how cycloplegia is used for refracting children.

A total of 2612 children aged 6 years and 1984 children aged 13 years were included. Of the two cohorts, median cycloplegic SER (IQR) was 1.00 D (0.50, 1.38) and -1.13 D (-2.63, 0.13) respectively, myopia prevalence was 5.2% and 61.0%, pseudomyopia prevalence was 24.1% and 18.9%, and median pseudomyopic power was 1.13 D (0.63, 1.63) and 0.38 D (0.13, 0.88). In both cohorts, greater baseline hyperopia was the strongest predictor of pseudomyopia (p<0.001), whereas time spent on near work was not associated with pseudomyopic power (p>0.05). After 1 year, 15.6% (98/629) of 6-year-olds and 10.7% (40/374) of 13-year-olds with pseudomyopia developed myopia. Compared with myopes, pseudomyopic children with the same pre-cycloplegic SER had slower myopic progression (p<0.001). Among all 127 optometry stores in Anyang, only 4 (3.15%) used cycloplegia for refracting children.

Pseudomyopia is more prevalent in younger, more hyperopic children. Pseudomyopia is not an independent risk factor for myopic progression in this setting.
Pseudomyopia is more prevalent in younger, more hyperopic children. Pseudomyopia is not an independent risk factor for myopic progression in this setting.Dopamine (DA) signals in the striatum are critical for a variety of vital processes, including motivation, motor learning, and reinforcement learning. Striatal DA signals can be evoked by direct activation of inputs from midbrain DA neurons (DANs) as well as cortical and thalamic inputs to the striatum. In this study, we show that in vivo optogenetic stimulation of prelimbic (PrL) and infralimbic (IL) cortical afferents to the striatum triggers an increase in extracellular DA concentration, which coincides with elevation of striatal acetylcholine (ACh) levels. This increase is blocked by a nicotinic ACh receptor (nAChR) antagonist. Using single or dual optogenetic stimulation in brain slices from male and female mice, we compared the properties of these PrL/IL-evoked DA signals with those evoked by stimulation from midbrain DAN axonal projections. PrL/IL-evoked DA signals are undistinguishable from DAN evoked DA signals in their amplitudes and electrochemical properties. However, PrL/IL-evoked DA signals are animals. Here we show that optogenetic stimulation of cortical glutamatergic afferents to the striatum triggers dopamine signals both in vivo and in vitro These afferents engage cholinergic interneurons, which drive dopamine release from dopamine neuron axons by activation of nicotinic acetylcholine receptors. We also show that cortically evoked dopamine signals have other unique properties, including spatial restriction and sensitivity to temperature changes than dopamine signals evoked by stimulation of midbrain dopamine neuron axons.γ-frequency oscillations (30-120 Hz) in cortical networks influence neuronal encoding and information transfer, and are disrupted in multiple brain disorders. While synaptic inhibition is important for synchronization across the γ-frequency range, the role of distinct interneuronal subtypes in slow ( less then 60 Hz) and fast γ states remains unclear. Here, we used optogenetics to examine the involvement of parvalbumin-expressing (PV+) and somatostatin-expressing (SST+) interneurons in γ oscillations in the mouse hippocampal CA3 ex vivo, using animals of either sex. Disrupting either PV+ or SST+ interneuron activity, via either photoinhibition or photoexcitation, led to a decrease in the power of cholinergically induced slow γ oscillations. Furthermore, photoexcitation of SST+ interneurons induced fast γ oscillations, which depended on both synaptic excitation and inhibition. Our findings support a critical role for both PV+ and SST+ interneurons in slow hippocampal γ oscillations, and further suggest that intense activation of SST+ interneurons can enable the CA3 circuit to generate fast γ oscillations.SIGNIFICANCE STATEMENT The generation of hippocampal γ oscillations depends on synchronized inhibition provided by GABAergic interneurons. Parvalbumin-expressing (PV+) interneurons are thought to play the key role in coordinating the spike timing of excitatory pyramidal neurons, but the role distinct inhibitory circuits in network synchronization remains unresolved. Here, we show, for the first time, that causal disruption of either PV+ or somatostatin-expressing (SST+) interneuron activity impairs the generation of slow γ oscillations in the ventral hippocampus ex vivo We further show that SST+ interneuron activation along with general network excitation is sufficient to generate high-frequency γ oscillations in the same preparation. These results affirm a crucial role for both PV+ and SST+ interneurons in hippocampal γ oscillation generation.
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