Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

Impact of Z score system on the management of coronary artery lesions in Kawasaki disease.

BACKGROUND: Coronary artery aneurysms are well-described in Kawasaki disease and the Multisystem Inflammatory Syndrome in Children and are graded using Z scores. Three Z score systems (Boston, Montreal, and DC) are widely used in North America. The recent Pediatric Heart Network Z score system is derived from the largest diverse sample to-date. The impact of Z score system on the rate of coronary dilation and management was assessed in a large real-world dataset. METHODS: Using a combined dataset of patients with acute Kawasaki disease from the Children's Hospital at Montefiore and the National Heart, Lung, and Blood Institute Kawasaki Disease Study, coronary Z scores and the rate of coronary lesions (Z ≥ 2.0) and aneurysms (Z ≥ 2.5) were determined using four Z score systems. Agreement among Z scores and the effect on Kawasaki management were assessed. RESULTS: Of 333 patients analysed, 136 were from Montefiore and 197 from the Kawasaki Disease Study. Age, sex, body surface area, and rate of coronary lesions did not differ between the samples. Among the four Z score systems, the rate of acute coronary lesions varied from 24 to 55%. The mean left anterior descending Z scores from Pediatric Heart Network and Boston had a large uniform discrepancy of 1.3. Differences in Z scores among the four systems may change anticoagulation management in up to 22% of a Kawasaki population. CONCLUSIONS: Choice of Z score system alone may impact Kawasaki disease diagnosis and management. Further research is necessary to determine the ideal coronary Z score system.

Contrasting cellular damage after Blue-IRIS and Femto-LASIK in cat cornea.

Blue-intra-tissue refractive index shaping (Blue-IRIS) is a new approach to laser refractive correction of optical aberrations in the eye, which alters the refractive index of the cornea rather than changing its shape. Before it can be implemented in humans, it is critical to establish whether and to what extent, Blue-IRIS damages the cornea. Here, we contrasted the impact of -1.5 D cylinder refractive corrections inscribed using either Blue-IRIS or femtosecond laser in-situ keratomileusis (femto-LASIK) on corneal cell viability. Blue-IRIS was used to write a -1.5 D cylinder gradient index (GRIN) lens over a 2.5 mm by 2.5 mm area into the mid-stromal region of the cornea in six freshly-enucleated feline eyes. The same correction (-1.5 D cylinder) was inscribed into another four cat eyes using femto-LASIK. Six hours later, all corneas were processed for histology and stained for terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) and p-γ-H2AX to label damaged cells. In Blue-IRIS-treated corneas, no tissue was removed and TUNEL-stained cells were confined to the laser focal zone in the stroma. In femto-LASIK, photoablation removed 14 µm of anterior stroma, but in addition, TUNEL-positive cells clustered across the femto-flap, the epithelium at the flap edges and the stroma below the ablation zone. Keratocytes positive for p-γ-H2AX were seen adjacent to all Blue-IRIS focal zones, but were completely absent from femto-LASIK-treated corneas. Unlike femto-LASIK, Blue-IRIS attains refractive correction in the cornea without tissue removal and only causes minimal, localized keratocyte death within the laser focal zones. In addition, Blue-IRIS induced DNA modifications associated with phosphorylation of γ-H2AX in keratocytes adjacent to the laser focal zones. We posit that this p-γ-H2AX response is related to alterations in chromatin structure caused by localized changes in osmolarity, a possible mechanism for the induced refractive index changes.