The notion that all protein functions are determined through macromolecular interactions is the driving force behind current efforts that aim to solve the structures of all cellular complexes. Recent findings, however, demonstrate a significant amount of structural disorder or polymorphism in protein complexes, a phenomenon that has been largely overlooked thus far. It is our view that such disorder can be classified into four mechanistic categories, covering a continuous spectrum of structural states from static to dynamic disorder and from segmental to full disorder. To emphasize its generality and importance, we suggest a generic term, ‘fuzziness’, for this phenomenon. Given the crucial role of protein disorder in protein–protein interactions and in regulatory processes, we envision that fuzziness will become integral to understanding the interactome.
Neuroelectric oscillations reflect rhythmic shifting of neuronal ensembles between high and low excitability states. In natural settings, important stimuli often occur in rhythmic streams, and when oscillations entrain to an input rhythm their high excitability phases coincide with events in the stream, effectively amplifying neuronal input responses. When operating in a ‘rhythmic mode’, attention can use these differential excitability states as a mechanism of selection by simply enforcing oscillatory entrainment to a task-relevant input stream. When there is no low-frequency rhythm that oscillations can entrain to, attention operates in a ‘continuous mode’, characterized by extended increase in gamma synchrony. We review the evidence for early sensory selection by oscillatory phase-amplitude modulations, its mechanisms and its perceptual and behavioral consequences.
Several theories have proposed possible functions of adult neurogenesis in learning processes on a systems level, such as the avoidance of catastrophic interference and the encoding of temporal and contextual information, and in emotional behavior. Under the assumption of such functionality of new neurons, the question arises: what are the consequences of adult hippocampal neurogenesis beyond the temporally immediate computational benefit? What might provide the evolutionary advantage of maintaining neurogenesis in the dentate gyrus but almost nowhere else? I propose that over the course of life, activity-dependently regulated adult neurogenesis reveals its true significance in the retained ability for lasting and cumulative network adaptations. The hippocampal precursor cells that generate new neurons with their particular acute function represent a ‘neurogenic reserve’: the potential to remain flexible and plastic in hippocampal learning when the individual is exposed to novelty and complexity.
The pursuit for drugs that inhibit cyclin-dependent kinases (CDKs) has been an intense area of research for more than 15 years. The first-generation inhibitors, Flavopiridol and CY-202, are in late-stage clinical trials, but so far have demonstrated only modest activity. Several second-generation inhibitors are now in clinical trials. Future approaches to determine clinical benefit need to incorporate both the lessons learned from these early compounds and information recently obtained from the genetic analysis of CDKs in preclinical models. Here we discuss key concepts that should be considered when validating the clinical utility of CDK inhibitors in cancer therapy.
Antisocial aggression is a widespread and expensive social problem. Although aggressive behaviors and temperament are highly heritable, clinical and trait associations for the most promising candidate gene for aggression, MAOA , have been largely inconsistent. We suggest that limitations inherent to that approach might be overcome by using multimodal neuroimaging to characterize neural mechanisms of genetic risk. Herein, we detail functional, structural and connectivity findings implicating the low-expressing allele of the MAOA u-VNTR ( MAOA -L) in adversely prejudicing information processing within a corticolimbic circuit composed of amygdala, rostral cingulate and medial prefrontal cortex. We propose that the MAOA-L, by causing an ontogenic excess of 5-hydroxytryptamine, labilizes critical neural circuitry for social evaluation and emotion regulation (the ‘socioaffective scaffold’), thereby amplifying the effects of adverse early-life experience and creating deleterious sociocognitive biases. Our construct provides a neurobiologically consistent model for gene–environment interactions in impulsive aggression.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level by either degradation or translational repression of a target mRNA. More than 400 miRNAs have been identified in the human genome, but the relevance of most of them to physiological and pathological processes remains unclear. Although downregulation of the miRNA-processing enzymes Dicer and Drosha is known to impair angiogenesis, only a few specific miRNAs targeting endothelial cell function and angiogenesis have been identified. miR-221 and miR-222 block endothelial cell migration, proliferation and angiogenesis in vitro by targeting the stem cell factor receptor c-Kit and indirectly regulating expression of endothelial nitric oxide synthase. A pro-angiogenic function has been established for the miR-17-92 cluster, which promotes tumor angiogenesis in vivo . Expression of let7-f and miR-27b contributes to in vitro angiogenesis. We review recent studies on the involvement of miRNA in angiogenesis and discuss their implications for miRNA-based therapeutic strategies targeting this process in disease.
Dimerization is fairly common in the G-protein-coupled receptor (GPCR) superfamily. First attempts to rationalize this phenomenon gave rise to an idea that two receptors in a dimer could be necessary to bind a single molecule of G protein or arrestin. Although GPCRs, G proteins and arrestins were crystallized only in their inactive conformations (in which they do not interact), the structures appeared temptingly compatible with this beautiful model. However, it did not survive the rigors of experimental testing: several recent studies unambiguously demonstrated that one receptor molecule is sufficient to activate a G protein and bind arrestin. Thus, to figure out the biological role of receptor self-association we must focus on other functions of GPCRs at different stages of their functional cycle.
Multiple neurochemical pathways are involved in mediating craving and relapse to alcohol. Opioidergic and glutamatergic systems have a key role in alcoholism, as demonstrated by the clinically effective compounds naltrexone and acamprosate acting through these systems. The dopaminergic system has long featured in alcoholism research; hitherto disappointing results from clinical studies could improve following the discovery that dopamine D3 receptor antagonism produces consistent and robust results in preclinical studies. Corticotropin-releasing factor signalling and the endocannabinoid system integrate stress-related events and thereby mediate relapse behaviour. Overall, these new targets have yielded several compounds that are undergoing clinical testing. However, the heterogeneity in treatment response makes it necessary to characterize genetic and protein markers and endophenotypes for individualized pharmacotherapy.
The class B family of G-protein-coupled receptors (GPCRs) regulates essential physiological functions such as exocrine and endocrine secretions, feeding behaviour, metabolism, growth, and neuro- and immuno-modulations. These receptors are activated by endogenous peptide hormones including secretin, glucagon, vasoactive intestinal peptide, corticotropin-releasing factor and parathyroid hormone. We have identified a common structural motif that is encoded in all class B GPCR-ligand N-terminal sequences. We propose that this local structure, a helix N-capping motif, is formed upon receptor binding and constitutes a key element underlying class B GPCR activation. The folded backbone conformation imposed by the capping structure could serve as a template for a rational design of drugs targeting class B GPCRs in several diseases.