Craniosynostosis, the fusion of one or more of the sutures of the skull vault before the brain completes its growth, is a common (1 in 2,500 births) craniofacial abnormality, ≈20% of which occurrences are caused by gain-of-function mutations in FGF receptors (FGFRs). We describe a genetic and pharmacological approach for the treatment of a murine model system of Crouzon-like craniosynostosis induced by a dominant mutation in Fgfr2c. Using genetically modified mice, we demonstrate that premature fusion of sutures mediated by Crouzon-like activated Fgfr2c mutant is prevented by attenuation of signaling pathways by selective uncoupling between the docking protein Frs2α and activated Fgfr2c, resulting in normal skull development. We also demonstrate that attenuation of Fgfr signaling in a calvaria organ culture with an Fgfr inhibitor prevents premature fusion of sutures without adversely affecting calvaria development. These experiments show that attenuation of FGFR signaling by pharmacological intervention could be applied for the treatment of craniosynostosis or other severe bone disorders caused by mutations in FGFRs that currently have no treatment.

The small subpopulation of high-affinity EGF receptors (EGFRs) on living cells revealed by Scatchard analysis of ¹²⁵ I-EGF binding results was discovered nearly three decades ago, yet not much is known about the underlying mechanism. After the determination of the structure of different forms of EGFR extracellular domain it was proposed that the monomeric tethered configuration corresponds to the majority of low-affinity receptors, whereas the extended dimeric configuration corresponds to the minority of the high-affinity class of EGFRs. Mathematical modeling of EGF-binding experiments to different conformational mutants of EGFR has shown that the high-affinity class of EGFR on living cells does not correspond to the extended configuration of EGFR and can only be accounted for by including in the mathematical model an additional binding event that is attributed to the dynamic nature of EGFR on living cells. To circumvent this problem we have performed similar experiments in the background of an EGFR mutant that does not form high-affinity sites. Quantitative analysis and mathematical modeling of these data show that release of the intramolecular tether causes a 2-fold increase in EGF-binding affinity, whereas elimination of the dimerization arm reduces EGF-binding affinity by ≈6-fold. These experiments confirm the salient features of the structural model for EGFR regulation and argue further that the intramolecular tether provides only limited autoinhibitory control of EGFR activity and that the low-affinity class of EGF-binding sites on living cells reflects interconverting, tethered, and extended receptor configurations.

Since the first years of history, microbial fermentation products such as bread, wine, yogurt and vinegar have always been noteworthy regarding their nutritional and health effects. Similarly, mushrooms have been a valuable food product in point of both nutrition and medicine due to their rich chemical components. Alternatively, filamentous fungi, which can be easier to produce, play an active role in the synthesis of some bioactive compounds, which are also important for health, as well as being rich in protein content. Therefore, this review presents some important bioactive compounds (bioactive peptides, chitin/chitosan, β-glucan, gamma-aminobutyric acid, L-carnitine, ergosterol and fructooligosaccharides) synthesized by fungal strains and their health benefits. In addition, potential probiotic- and prebiotic fungi were researched to determine their effects on gut microbiota. The current uses of fungal based bioactive compounds for cancer treatment were also discussed. The use of fungal strains in the food industry, especially to develop innovative food production, has been seen as promising microorganisms in obtaining healthy and nutritious food. Graphical Abstract

Purpose. To investigate the role of the serine/threonine kinase SIK2, a member of the salt-inducible kinase (SIK) family, in insulin-dependent cell survival and hyperglycemia-induced cell death in Müller glia. Methods. Expression studies were performed by RT-PCR, immunostaining, Northern blotting, and immunoblotting. Insulin-dependent changes in SIK2 activity were investigated by in vitro kinase assays in MIO-M1 Müller cell line. Akt activation was studied by immunoblotting and cell death by TUNEL assay. The potential role of SIK2 in insulin signaling was explored by overexpression and sh-RNA knock-down approaches. Effects of hyperglycemia were studied in vitro and in vivo in streptozotocin-injected rats. Results. SIK2 expression was detected throughout adult retina, except for the outer nuclear layer. Insulin stimulation of MIO-M1 cells resulted in a rapid 2-fold increase of SIK2 activity, increased insulin receptor substrate 1 (IRS1)-SIK2 interaction, and reduced cell death. pAkt levels following insulin treatment were modulated by SIK2 activity. Under hyperglycemia, increased SIK2 activity/expression was concomitant to decreased Akt activation and enhanced apoptosis; whereas knockdown of SIK2 under normo- and hyperglycemic conditions resulted in a rapid increase in pAkt levels and blunted cell death. SIK2 overexpression under normoglycemia had an opposite effect. SIK2 activity increased significantly within 2 weeks of induction of hyperglycemia in the rat retina. Conclusions. Results indicate that SIK2 functions as a negative modulator of the insulin-dependent survival pathway and contributes to hyperglycemia-induced cell death of Müller glia in vitro. Although still hypothetical at this point, our study suggests that SIK2 could serve a similar role during the development of diabetic retinopathy in vivo and that it represents a potential target to control disease progression.