Mature miRNAs are 19–24 nucleotide noncoding RNAs that post-transcriptionally regulate gene expression in living cells by mediating targeted hydrolysis and translation inhibition of mRNAs. In recent years, miRNAs have been detected in a variety of biological fluids as extracellular nuclease-resistant entities. Importantly, extracellular circulating miRNAs are aberrantly expressed in blood plasma or serum during the course of many diseases, including cancer, and are promising noninvasive biomarkers. However, the biological function of extracellular miRNAs remains questionable. In this article, we summarise the current theories regarding extracellular miRNA origin and function, and suggest that these miRNAs are mostly byproducts of cellular activity. Nevertheless, some extracellular miRNA species might also carry cell–cell signaling function.
A basic feature of intelligent systems such as the cerebral cortex is the ability to freely associate aspects of perceived experience with an internal representation of the world and make predictions about the future. Here, a hypothesis is presented that the extraordinary performance of the cortex derives from an associative mechanism built in at the cellular level to the basic cortical neuronal unit: the pyramidal cell. The mechanism is robustly triggered by coincident input to opposite poles of the neuron, is exquisitely matched to the large- and fine-scale architecture of the cortex, and is tightly controlled by local microcircuits of inhibitory neurons targeting subcellular compartments. This article explores the experimental evidence and the implications for how the cortex operates.
Information that is congruent with existing knowledge (a schema) is usually better remembered than less congruent information. Only recently, however, has the role of schemas in memory been studied from a systems neuroscience perspective. Moreover, incongruent (novel) information is also sometimes better remembered. Here, we review lesion and neuroimaging findings in animals and humans that relate to this apparent paradoxical relationship between schema and novelty. In addition, we sketch a framework relating key brain regions in medial temporal lobe (MTL) and medial prefrontal cortex (mPFC) during encoding, consolidation and retrieval of information as a function of its congruency with existing information represented in neocortex. An important aspect of this framework is the efficiency of learning enabled by congruency-dependent MTL–mPFC interactions.
Fragment-based drug discovery (FBDD) has become established in both industry and academia as an alternative approach to high-throughput screening for the generation of chemical leads for drug targets. In FBDD, specialised detection methods are used to identify small chemical compounds (fragments) that bind to the drug target, and structural biology is usually employed to establish their binding mode and to facilitate their optimisation. In this article, we present three recent and successful case histories in FBDD. We then re-examine the key concepts and challenges of FBDD with particular emphasis on recent literature and our own experience from a substantial number of FBDD applications. Our opinion is that careful application of FBDD is living up to its promise of delivering high quality leads with good physical properties and that in future many drug molecules will be derived from fragment-based approaches.
A recent paradigm shift in systems neuroscience is the division of the human brain into functional networks. Functional networks are collections of brain regions with strongly correlated activity both at rest and during cognitive tasks, and each network is believed to implement a different aspect of cognition. We propose here that anxiety disorders and high trait anxiety are associated with a particular pattern of functional network dysfunction: increased functioning of the cingulo-opercular and ventral attention networks as well as decreased functioning of the fronto-parietal and default mode networks. This functional network model can be used to differentiate the pathology of anxiety disorders from other psychiatric illnesses such as major depression and provides targets for novel treatment strategies.
Caspase-3 has been identified as a key mediator of neuronal programmed cell death. This protease plays a central role in the developing nervous system and its activation is observed early in neural tube formation and persists during postnatal differentiation of the neural network. Caspase-3 activation, a crucial event of neuronal cell death program, is also a feature of many chronic neurodegenerative diseases. This traditional apoptotic function of caspase-3 is challenged by recent studies that reveal new cell death-independent roles for mitochondrial-activated caspase-3 in neurite pruning and synaptic plasticity. These findings underscore the need for further research into the mechanism of action and functions of caspase-3 that may prove useful in the development of novel pharmacological treatments for a diverse range of neurological disorders.
Mitochondria, the powerhouses of the cell, import most of their proteins from the cytosol. It was originally assumed that mitochondria imported precursor proteins via a general pathway but recent studies have revealed a remarkable variety of import pathways and mechanisms. Currently, five different protein import pathways can be distinguished. However, the import machineries cooperate with each other and are connected to other systems that function in the respiratory chain, mitochondrial membrane organization, protein quality control and endoplasmic reticulum-mitochondria junctions. In this Opinion, we propose that mitochondrial protein import should not be seen as an independent task of the organelle and that a network of cooperating machineries is responsible for major mitochondrial functions.
Association between signaling proteins and their cellular targets is generally thought to be highly specific (implicating a high association constant, ) and, at the same time, transient or short-lived (corresponding to a high dissociation rate constant, ). However, a combination of high and high would lead to a high association rate constant ( = ), which poses a problem because there is a limit to which can be increased, set by the diffusional approach to form the complex. In this Opinion article, I propose that having the signaling protein disordered before binding to the target provides a way out of this quandary. The intrinsic disorder of the signaling protein would decrease without sacrificing the specificity of the complex, and thus would allow to be increased to a range appropriate for signaling.
Nascent polypeptides entering the endoplasmic reticulum (ER) are covalently modified with pre-assembled oligosaccharides. The terminal glucose and mannose residues are immediately removed after transfer of the oligosaccharide onto newly synthesized polypeptides. This processing determines whether the polypeptide will be retained in the ER, transported along the secretory pathway, or dislocated across the ER membrane for destruction. New avenues of research and some issues of controversy have recently been opened by the discovery that lectin–oligosaccharide interactions stabilize supramolecular complexes between regulators of ER-associated degradation (ERAD). In this Opinion article, we propose a unified model that depicts carbohydrates acting both as flags signaling the fitness of a maturing protein and as docking sites that regulate the assembly and stability of the ERAD machinery.
Endocytosis participates in downregulating incoming signals, but ‘signaling endosomes’ may also serve as physical platforms for crosstalk between signaling pathways. Here, we briefly review the role of endosomes in signaling crosstalk and suggest that endosome-associated scaffold proteins mediate this crosstalk. In addition, using a proteome-wide in silico approach – in which we analyze endosome-binding properties and the capacity of candidates to recruit signaling proteins from more than one distinct pathway – we extend the list of putative crosstalk-mediating endosomal scaffolds. Because endosomal crosstalk may be an important systems-level regulator of pathway communication, scaffold proteins that mediate this crosstalk could be potential targets for pharmacological intervention and synthetic engineering.