Magic™ Anti-PhosphoY (Phospho Y) polyclonal antibody

Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of "from population to neuron", combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major mental illnesses. We hypothesized that molecules associated with insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2 tyrosine phosphorylation upon insulin stimulation, indicative of insulin resistance. These cells also displayed an upregulation of IRS1 protein phosphorylation at serine-312 at baseline (without insulin stimulation), further supporting the concept of insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to amphetamine, which is also observed in some patients with major mental illnesses. The bi-directional relationships between major mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with insulin resistance underlying these mental and physical conditions.

Anaplastic lymphoma kinase (ALK) has been thought to be a prospective target of anti-drug resistance design in treatment of tumors and specific neuron diseases. It is highly useful for the seeking of possible strategy alleviating drug resistance to probe the mutation-mediated effect on binding of inhibitors to ALK. In the current work, multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations, molecular mechanics generalized Born surface area (MM-GBSA) and free energy landscapes were coupled to explore influences of mutations L1198F, L1198F/C1156Y, and C1156Y on the binding of the first ALK inhibitor crizotinib to ALK. The results suggest that three mutations obviously affect structural flexibility, motion modes and conformational changes of ALKs. L1198F and L1198F/C1156Y strengthen the binding of crizotinib to the mutated ALKs but C1156Y induces evident drug resistance toward crizotinib. Analyses of free energy landscapes show that stability in the orientation and positions of crizotinib relative to ALK plays a vital role in alleviating drug resistance of mutations toward crizotinib. Residue-based free energy decomposition method was utilized to evaluate the contributions of separate residues to the binding of crizotinib. The results not only indicate that the tuning of point mutation L1198F on interaction networks of crizotinib with ALK can be regarded as a possible strategy to relieve drug resistance of the mutated ALK but also further verify that residues L1122, V1130, L1196, L1198, M1199, and L1256 can be used as efficient targets of anti-drug resistance design induced by mutations.