Targeted mass spectrometry (MS) is becoming widely used in academia and in pharmaceutical and biotechnology industries for sensitive and quantitative detection of proteins, peptides and post-translational modifications. In Nature methods, Gillette and Carr describe the increasing importance of targeted MS technologies in clinical proteomics and the potential key roles these techniques will have in bridging biomedical discovery and clinical implementation.
Michael A Gillette & Steven A Carr
Scientists reverse engineer fluorescent proteins for light-mediated control.
Optogenetics is a young discipline that is coming on strong in fields such as neuroscience and protein signaling. It refers to the use of light-sensitive proteins to control cellular processes in living cells and organisms. Optogenetic tools can also be used to sense biological processes. Each of these applications has been performed with separate protein tools—until now. Michael Lin, at Stanford University, and his colleagues have adapted a fluorescent protein (FP) to act as a light switch for controlling protein interactions, creating a protein tool that can both mediate biological function and report its own activity.
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.
Steve Chang et. al. studied encoding of the outcomes of social decisions in three frontal cortical areas as monkeys performed a social reward allocation task. Orbitofrontal cortex neurons signaled received rewards, anterior cingulate (ACC) sulcus neurons signaled foregone rewards, and the ACC gyrus was involved in the computation of shared experience and social reward.
Nature Neuroscience (2012) doi:10.1038/nn.3287
Cerebrocortical injuries such as stroke are a major source of disability. Maladaptive consequences can result from post-injury local reorganization of cortical circuits. For example, epilepsy is a common sequela of cortical stroke, but the mechanisms responsible for seizures following cortical injuries remain unknown. In addition to local reorganization, long-range, extra-cortical connections might be critical for seizure maintenance. In rats, researchers found that the thalamus, a structure that is remote from, but connected to, the injured cortex, was required to maintain cortical seizures. Thalamocortical neurons connected to the injured epileptic cortex underwent changes in HCN channel expression and became hyperexcitable. Targeting these neurons with a closed-loop optogenetic strategy revealed that reducing their activity in real-time was sufficient to immediately interrupt electrographic and behavioral seizures. This approach is of therapeutic interest for intractable epilepsy, as it spares cortical function between seizures, in contrast with existing treatments, such as surgical lesioning or drugs. Lian Han et al.
A method for tagging single transcripts with two fluorescent markers can be used to study many aspects of gene expression, including intrinsic noise in transcription or polymerase dynamics at a single gene, report Singer and colleagues.
Lian Han et al. Nature Neuroscience (2012) doi:10.1038/nn.3289
Dorsal root ganglion neurons respond to both painful and itchy stimuli, but are there itch-specific neurons? Here the authors describe a group of MrgprA3-expressing neurons that innervate the superficial layers of the skin and selectively sense itch.
The model fit implies that the age of the universe is 13.772+/-0.059 Gyr, and the fit Hubble constant is H0 = 69.32+/-0.80 km/s/Mpc. Inflation is also supported: the fluctuations are adiabatic, with Gaussian random phases; the detection of a deviation of the scalar spectral index from unity reported earlier by WMAP now has high statistical significance (n_s = 0.9608+/-0.0080); and the universe is close to flat/Euclidean, Omega_k = -0.0027 (+0.0039/-0.0038). Overall, the WMAP mission has resulted in a reduction of the cosmological parameter volume by a factor of 68,000 for the standard six-parameter LCDM model, based on CMB data alone.
An international team, led by researchers from UC San Diego, has discovered that "random" mutations in the genome are not quite so random after all. Their study, to be published in the journal Cell on December 21, shows that the DNA sequence in some regions of the human genome is quite volatile and can mutate ten times more frequently than the rest of the genome. Genes that are linked to autism and a variety of other disorders have a particularly strong tendency to mutate. Science Daily, Dec 20, 2012
Jacob J. Michaelson et al.
Cell, Volume 151, Issue 7, 1431-1442, 21 December 2012
In Nature Neuroscience January 2013 issue, Moshe Szyf explains the environmental interaction onto genes. A report elucidates the widely recognized, but poorly understood, concept of gene-environment interaction, finding a molecular mechanism in the case of post-traumatic stress disorder: demethylation of a glucocorticoid response element in the stress response regulator FKBP5 that depends on both the risk allele and childhood trauma. Moshe SzyfNature Neuroscience 16, 2–4 (2013) doi:10.1038/nn.3286
Since the original characterization of the ventral visual pathway, our knowledge of its neuroanatomy, functional properties, and extrinsic targets has grown considerably. Here the authors synthesize this recent evidence and propose that the ventral pathway is best understood as a recurrent occipitotemporal network containing neural representations of object quality both utilized and constrained by at least six distinct cortical and subcortical systems. Each system serves its own specialized behavioral, cognitive, or affective function, collectively providing the raison d’être for the ventral visual pathway. This expanded framework contrasts with the depiction of the ventral visual pathway as a largely serial staged hierarchy culminating in singular object representations and more parsimoniously incorporates attentional, contextual, and feedback effects.
A coherent pathway -- which starts from no more than rocks, water and carbon dioxide and leads to the emergence of the strange bio-energetic properties of living cells -- has been traced for the first time in a major hypothesis paper in Cell this week.
Science Daily on Dec. 20, 2012 Reference : Nick Lane, William F. Martin. The Origin of Membrane Bioenergetics. Cell, 2012; 151 (7): 1406
It's not how smart students are but how motivated they are and how they study that determines their growth in math achievement. That's the main finding of a new study that appears in the journal Child Development.
The study was conducted by researchers at the University of Munich and the University of Bielefeld. "While intelligence as assessed by IQ tests is important in the early stages of developing mathematical competence, motivation and study skills play a more important role in students' subsequent growth," according to Kou Murayama, postdoctoral researcher of psychology at the University of California, Los Angeles (who was at the University of Munich when he led the study).
Scientists have been surprised by the unexpected discovery of a nearby solar system using a new experimental technique. The system of five planets ranging in size from two to six times the Earth's mass orbiting the Sun-like star Tau Ceti, just 12 light years away. ABC News http://arxiv.org/abs/1212.4058
Although different genes evolve at different rates, when complete sets of orthologous genes are considered across taxa, the distribution of rates is remarkably conserved. That is, the differences in the rates of evolution among genes in a genome remain consistent. A potential explanation for this observation is the molecular clock, which is a model that has been used widely in phylogenetics. Now, Koonin and colleagues show that available phylogenetic data are more compatible with an alternative model that they propose termed the universal pacemaker (UPM).
Reaching out to high five someone, grasping and moving objects of different shapes and sizes, feeding herself dark chocolate. For Jan Scheuermann and a team of researchers from the University of Pittsburgh School of Medicine and UPMC, accomplishing these seemingly ordinary tasks demonstrated for the first time that a person with longstanding quadriplegia can maneuver a mind-controlled, human-like robot arm in seven dimensions (7D) to consistently perform many of the natural and complex motions of everyday life. UPMC/University of Pittsburgh Schools of the Health Sciences, News release on Dec 16, 2012
How many matter particles exist in nature? Particle physicists have been dealing with this question for a long time. The 12 matter particles contained in the standard model of particle physics? Or are there further particles with too high a mass to be produced by the experiments performed so far? These questions are now answered by researchers of KIT, CERN, and Humboldt University in the current issue of the Physical Review Letters
Fossils found in rocks of the Ediacaran period in Australia have been previously characterized as early marine organisms. But a report suggests that these rocks are fossilized soils. So did some of these Ediacaran organisms in fact live on land, like lichens? A palaeontologist and a geologist weigh up the evidence.
Shuhai Xiao & L. Paul Knauth Nature 493, 28–29 (03 January 2013) doi:10.1038/nature11765nline 12 December 2012
Asteroid that killed the dinosaurs also wiped out the ‘Obamadon’, The asteroid collision widely thought to have killed the dinosaurs also led to extreme devastation among snake and lizard species, according to new research — including the extinction of a newly identified lizard Yale and Harvard scientists have named Obamadon gracilis. The published paper can be fund here.
Understanding the mechanisms underlying the many forms of vertebrate behavior is a central objective of neuroscience and, although studied extensively at the cellular and circuit levels, very little is known about the underlying molecular evolutionary events. How did genome evolution give rise to the many forms of learning, emotional behavior and motor functions and generate the subtlety of synaptic regulation that is manifest in the mammalian brain?
Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C-terminal domains (CTDs). To identify shared ancestral functions and diversified subunit-specific functions, the authors exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock-in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit-specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long-term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 genes.
Despite the prevailing idea that neurogliaform cells produce a spatially unrestricted widespread inhibition, the authors demonstrate here that their activity attenuates thalamic-evoked feed-forward inhibition in layer IV barrel cortex but has no effect on feed-forward excitation. The result of this circuit selectivity is a dynamic regulation in the temporal window for integration of excitatory thalamic input, thus revealing a new role for neurogliaform cells in shaping sensory processing.
Ramesh Chittajallu, Kenneth A Pelkey & Chris J McBain
Whereas large-scale efforts have rapidly advanced the understanding and practical impact of human genomic variation, the practical impact of variation is largely unexplored in the human microbiome. The authors developed a framework for metagenomic variation analysis and applied it to 252 faecal metagenomes of 207 individuals from Europe and North America. Using 7.4 billion reads aligned to 101 reference species, they detected 10.3 million single nucleotide polymorphisms (SNPs), 107,991 short insertions/deletions, and 1,051 structural variants. The average ratio of non-synonymous to synonymous polymorphism rates of 0.11 was more variable between gut microbial species than across human hosts. Subjects sampled at varying time intervals exhibited individuality and temporal stability of SNP variation patterns, despite considerable composition changes of their gut microbiota. This indicates that individual-specific strains are not easily replaced and that an individual might have a unique metagenomic genotype, which may be exploitable for personalized diet or drug intake.
The origins and evolution of higher cognitive functions, including complex forms of learning, attention and executive functions, are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 million years ago) was genome duplication and subsequent diversification of postsynaptic genes. Here the authors report the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in each of the four Dlg paralogs showed that simple associative learning required Dlg4, whereas Dlg2 and Dlg3 diversified to have opposing functions in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed that Dlg2's role in complex learning, cognitive flexibility and attention has been highly conserved over 100 million years. Dlg-family mutations underlie psychiatric disorders, suggesting that genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness.
Jess Nithianantharajah, et al. Nature Neuroscience 16, 16–24 (2013) doi:10.1038/nn.3276
Genetic and environmental factors control morphological and functional differences between the two sides of the nervous system. Neural asymmetries are proposed to have important roles in circuit physiology, cognition and species-specific behaviours. We propose two fundamentally different mechanisms for encoding left–right asymmetry in neural circuits. In the first, asymmetric circuits share common components; in the second, there are unique unilateral structures. Research in both vertebrates and invertebrates is helping to reveal the mechanisms underlying the development of neural lateralization, but less is known about the function of circuit asymmetries. Technical advances in the coming years are likely to revolutionize our understanding of left–right asymmetry in the nervous system.