Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase

Human thymidylate synthase is a homodimeric enzyme that plays a key role in DNA synthesis and is a target for several clinically important anticancer drugs that bind to its active site. We have designed peptides to specifically target its dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, and calorimetric evidence that the peptides do indeed bind at the interface of the dimeric protein and stabilize its di-inactive form. The "LR" peptide binds at a previously unknown binding site and shows a previously undescribed mechanism for the allosteric inhibition of a homodimeric enzyme. It inhibits the intracellular enzyme in ovarian cancer cells and reduces cellular growth at low micromolar concentrations in both cisplatin-sensitive and -resistant cells without causing protein overexpression. This peptide demonstrates the potential of allosteric inhibition of hTS for overcoming platinum drug resistance in ovarian cancer.     

Alcohol consumption in mild cognitive impairment and dementia: harmful or neuroprotective?

Objective: In several longitudinal studies, light‐to‐moderate drinking of alcoholic beverages has been proposed as being protective against the development of age‐related changes in cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia). However, contrasting findings also exist. Method: The English literature published in this area before September 2011 was evaluated, and information relating to the various factors that may impact upon the relationship between alcohol consumption and dementia or predementia syndromes is presented in the succeeding texts. Results: Light‐to‐moderate alcohol consumption may be associated with a reduced risk of incident overall dementia and AD; however, protective benefits afforded to vascular dementia, cognitive decline, and predementia syndromes are less clear. The equivocal findings may relate to many of the studies being limited to cross‐sectional designs, restrictions by age or gender, or incomplete ascertainment. Different outcomes, beverages, drinking patterns, and study follow‐up periods or possible interactions with other lifestyle‐related (e.g., smoking) or genetic factors (e.g., apolipoprotein E gene variation) may all contribute to the variability of findings. Conclusion: Protective effects of moderate alcohol consumption against cognitive decline are suggested to be more likely in the absence of the AD‐associated apolipoprotein E ε4 allele and where wine is the beverage. At present, there is no indication that light‐to‐moderate alcohol drinking would be harmful to cognition and dementia, and attempts to define what might be deemed beneficial levels of alcohol intake in terms of cognitive performance would be highly problematic and contentious. Copyright © 2012 John Wiley & Sons, Ltd.     

Creatine affects in vitro electrophysiological maturation of neuroblasts and protects them from oxidative stress

Creatine (Cr) is a very popular ergogenic molecule that has recently been shown to have antioxidant properties. The effectiveness of Cr supplementation in treating neurological diseases and Cr deficiency syndromes has been demonstrated, and experimental reports suggest that it plays an important role in CNS development. In spite of this body of evidence, the role of Cr in functional and structural neuronal differentiation is still poorly understood. Here we used electrophysiological, morphological, and biochemical approaches to study the effects of Cr supplementation on in vitro differentiation of spinal neuroblasts under standard conditions or subjected to oxidative stress, a status closely related to perinatal hypoxia-ischemia, a severe condition for developing brain. Cr supplementation (10 and 20 mM) completely prevented the viability decrease and neurite development impairment induced by radical attack, as well as nonprotein sulphydryl antioxidant pool depletion. Similar results were obtained using the antioxidant trolox. Furthermore, Cr supplementation induced a significant and dose-dependent anticipation of Na(+) and K(+) current expression during the period of in vitro network building. Consistently with the latter finding, higher excitability, expressed as number of spikes following depolarization, was found in supplemented neuroblasts. All effects were dependent on the cytosolic fraction of Cr, as shown using a membrane Cr-transporter blocker. Our results indicate that Cr protects differentiating neuroblasts against oxidative insults and, moreover, affects their in vitro electrophysiological maturation, suggesting possibly relevant effects of dietary Cr supplementation on developing CNS.     

Covert face recognition in congenital prosopagnosia: a group study

IntroductionEven though people with congenital prosopagnosia (CP) never develop a normal ability to “overtly” recognize faces, some individuals show indices of “covert” (or implicit) face recognition. The aim of this study was to demonstrate covert face recognition in CP when participants could not overtly recognize the faces.MethodsEleven people with CP completed three tasks assessing their overt face recognition ability, and three tasks assessing their “covert” face recognition: a Forced choice familiarity task, a Forced choice cued task, and a Priming task.ResultsEvidence of covert recognition was observed with the Forced choice familiarity task, but not the Priming task. In addition, we propose that the Forced choice cued task does not measure covert processing as such, but instead “provoked-overt” recognition.ConclusionsOur study clearly shows that people with CP demonstrate covert recognition for faces that they cannot overtly recognize, and that behavioural tasks vary in their sensitivity to detect covert recognition in CP.