Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model.

Down syndrome (DS) is a genetic disorder that causes cognitive impairment. The staggering effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We examined the neuron-astrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we discovered the functional defects of DS astroglia and their effects on neuronal excitability. Compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. Furthermore, suppressed neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100B, a calcium binding protein coded on HSA21. Our results suggest a mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability

Detection of Microregional Hypoxia in Mouse Cerebral Cortex by Two-photon Imaging of Endogenous NADH Fluorescence

The brain's ability to function at high levels of metabolic demand depends on continuous oxygen supply through blood flow and tissue oxygen diffusion. Here we present a visualized experimental and methodological protocol to directly visualize microregional tissue hypoxia and to infer perivascular oxygen gradients in the mouse cortex. It is based on the non-linear relationship between nicotinamide adenine dinucleotide (NADH) endogenous fluorescence intensity and oxygen partial pressure in the tissue, where observed tissue NADH fluorescence abruptly increases at tissue oxygen levels below 10 mmHg1. We use two-photon excitation at 740 nm which allows for concurrent excitation of intrinsic NADH tissue fluorescence and blood plasma contrasted with Texas-Red dextran. The advantages of this method over existing approaches include the following: it takes advantage of an intrinsic tissue signal and can be performed using standard two-photon in vivo imaging equipment; it permits continuous monitoring in the whole field of view with a depth resolution of ~50 μm. We demonstrate that brain tissue areas furthest from cerebral blood vessels correspond to vulnerable watershed areas which are the first to become functionally hypoxic following a decline in vascular oxygen supply. This method allows one to image microregional cortical oxygenation and is therefore useful for examining the role of inadequate or restricted tissue oxygen supply in neurovascular diseases and stroke

Towards a Learner-Centered Explainable AI: Lessons from the learning sciences

In this short paper, we argue for a refocusing of XAI around human learning goals. Drawing upon approaches and theories from the learning sciences, we propose a framework for the learner-centered design and evaluation of XAI systems. We illustrate our framework through an ongoing case study in the context of AI-augmented social work.Comment: 7 pages, 2 figure

Accelerated structural evolution of galaxies in a starbursting cluster at z=2.51

Structural properties of cluster galaxies during their peak formation epoch, $z \sim 2-4$ provide key information on whether and how environment affects galaxy formation and evolution. Based on deep HST/WFC3 imaging towards the z=2.51 cluster, J1001, we explore environmental effects on the structure, color gradients, and stellar populations of a statistical sample of cluster SFGs. We find that the cluster SFGs are on average smaller than their field counterparts. This difference is most pronounced at the high-mass end ($M_{\star} > 10^{10.5} M_{\odot}$) with nearly all of them lying below the mass-size relation of field galaxies. The high-mass cluster SFGs are also generally old with a steep negative color gradient, indicating an early formation time likely associated with strong dissipative collapse. For low-mass cluster SFGs, we unveil a population of compact galaxies with steep positive color gradients that are not seen in the field. This suggests that the low-mass compact cluster SFGs may have already experienced strong environmental effects, e.g., tidal/ram pressure stripping, in this young cluster. These results provide evidence on the environmental effects at work in the earliest formed clusters with different roles in the formation of low and high-mass galaxies.Comment: 13 pages, 10 figures, 1 tabl

Myocardial Injury, Obesity, and the Obesity Paradox

To examine whether pre-heart failure (HF) myocardial injury explains the differential mortality after HF across weight categories

Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions

Oxygen transport imposes a possible constraint on the brain's ability to sustain variable metabolic demands, but oxygen diffusion in the cerebral cortex has not yet been observed directly. We show that concurrent two-photon fluorescence imaging of endogenous nicotinamide adenine dinucleotide (NADH) and the cortical microcirculation exposes well-defined boundaries of tissue oxygen diffusion in the mouse cortex. The NADH fluorescence increases rapidly over a narrow, very low pO2 range with a p50 of 3.4±0.6 mm Hg, thereby establishing a nearly binary reporter of significant, metabolically limiting hypoxia. The transient cortical tissue boundaries of NADH fluorescence exhibit remarkably delineated geometrical patterns, which define the limits of tissue oxygen diffusion from the cortical microcirculation and bear a striking resemblance to the ideal Krogh tissue cylinder. The visualization of microvessels and their regional contribution to oxygen delivery establishes penetrating arterioles as major oxygen sources in addition to the capillary network and confirms the existence of cortical oxygen fields with steep microregional oxygen gradients. Thus, two-photon NADH imaging can be applied to expose vascular supply regions and to localize functionally relevant microregional cortical hypoxia with micrometer spatial resolution

Reduced haemodynamic response in the ageing visual cortex measured by absolute fNIRS

The effect of healthy ageing on visual cortical activation is still to be fully explored. This study aimed to elucidate whether the haemodynamic response (HDR) of the visual cortex altered as a result of ageing. Visually normal (healthy) participants were presented with a simple visual stimulus (reversing checkerboard). Full optometric screening was implemented to identify two age groups: younger adults (n = 12, mean age 21) and older adults (n = 13, mean age 71). Frequency-domain Multi-distance (FD-MD) functional Near-Infrared Spectroscopy (fNIRS) was used to measure absolute changes in oxygenated [HbO] and deoxygenated [HbR] haemoglobin concentrations in the occipital cortices. Utilising a slow event-related design, subjects viewed a full field reversing checkerboard with contrast and check size manipulations (15 and 30 minutes of arc, 50% and 100% contrast). Both groups showed the characteristic response of increased [HbO] and decreased [HbR] during stimulus presentation. However, older adults produced a more varied HDR and often had comparable levels of [HbO] and [HbR] during both stimulus presentation and baseline resting state. Younger adults had significantly greater concentrations of both [HbO] and [HbR] in every investigation regardless of the type of stimulus displayed (p<0.05). The average variance associated with this age-related effect for [HbO] was 88% and [HbR] 91%. Passive viewing of a visual stimulus, without any cognitive input, showed a marked age-related decline in the cortical HDR. Moreover, regardless of stimulus parameters such as check size, the HDR was characterised by age. In concurrence with present neuroimaging literature, we conclude that the visual HDR decreases as healthy ageing proceeds

Changes in serum proteomic patterns by presurgical alpha-tocopherol and L-selenomethionine supplementation in prostate cancer

BACKGROUND: Evidence of the chemopreventive effects of the dietary antioxidants alpha-tocopherol (vitamin E) and l-selenomethionine (selenium) comes from secondary analysis of two phase III clinical trials that found treatment with these antioxidants reduced the incidence of prostate cancer. To determine the effects of selenium and vitamin E in blood and prostate tissue, we undertook a preoperative feasibility study complementary to the currently ongoing Selenium and Vitamin E Cancer Prevention Trial. METHODS: Forty-eight patients with clinically localized prostate cancer enrolled on this 2 x 2 factorial design study were randomized to take selenium, vitamin E, both, or placebo for 3 to 6 weeks before prostatectomy. Sera were collected from patients before and after dietary supplementation. Thirty-nine patients were evaluable, and 29 age-matched disease-free men served as controls. Mass profiling of lipophilic serum proteins of lower molecular weight (2-13.5 kDa) was conducted, and mass spectra data were analyzed using custom-designed software. RESULTS: Weighted voting analyses showed a change in sera classification from cancerous to healthy for some patients with prostate cancer after dietary intervention. ANOVA analysis showed significantly different treatment effects on prediction strength changes among the four groups at a 95% confidence level. Eliminating an outlying value and performing post hoc analysis using Fisher\u27s least significant difference method showed that effects in the group treated with the combination were significantly different from those of the other groups. CONCLUSION: In sera from patients with prostate cancer, selenium and vitamin E combined induced statistically significant proteomic pattern changes associated with prostate cancer-free status