Localized application of SAG21k-loaded fibrin hydrogels for targeted modulation of the hedgehog pathway in facial nerve injury.

Given the broad biological effects of the Hedgehog (Hh) pathway, there is potential clinical value in local application of Hh pathway modulators to restrict pathway activation of target tissues and avoid systemic pathway activation. One option to limit Hh pathway activation is using fibrin hydrogels to deliver pathway modulators directly to tissues of interest, bypassing systemic distribution of the drug. In this study, we loaded the potent Hh pathway agonist, SAG21k, into fibrin hydrogels. We describe the binding between fibrin and SAG21k and achieve sustained release of the drug in vitro. SAG21k-loaded fibrin hydrogels exhibit strong biological activity in vitro, using a pathway-specific reporter cell line. To test in vivo activity, we used a mouse model of facial nerve injury. Application of fibrin hydrogels is a common adjunct to surgical nerve repair, and the Hh pathway is known to play an important role in facial nerve injury and regeneration. Local application of the Hh pathway agonist SAG21k using a fibrin hydrogel applied to the site of facial nerve injury successfully activates the Hh pathway in treated nerve tissue. Importantly, this method appears to avoid systemic pathway activation when Hh-responsive organs are analyzed for transcriptional pathway activation. This method of local tissue Hh pathway agonist administration allows for effective pathway targeting surgically accessible tissues and may have translational value in situations where supranormal pathway activation is therapeutic.

Dysfunctions associated with the intraparietal sulcus and a distributed network in individuals with math learning difficulties: An ALE meta-analysis.

Math learning difficulty (MLD) is a learning disorder characterized by persistent impairments in the understanding and application of numbers independent of intelligence or schooling. The current study aims to review existing neuroimaging studies to characterize the neurobiological basis in MLD for their quantity and arithmetic dysfunctions. We identified a total of 24 studies with 728 participants through the literature. Using the activation likelihood estimate (ALE) method, we found that the most consistent neurobiological dysfunction in MLD was observed in the right intraparietal sulcus (IPS) with distinct patterns of the anterior and posterior aspects. Meanwhile, neurobiological dysfunctions were also observed in a distributed network including the fusiform gyrus, inferior temporal gyrus, insula, prefrontal cortex, anterior cingulate cortex, and claustrum. Our results suggest a core dysfunction in the right anterior IPS and left fusiform gyrus with atypically upregulated functions in brain regions for attention, working memory, visual processing, and motivation, serving as the neurobiological basis of MLD.