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10.1073/pnas.0706792104	28,116,412	Biological signaling systems produce an output, such as the level of a phosphorylated protein, in response to defined input signals. The output level as a function of the input level is called the system's input–output relation. One may ask whether this input–output relation is sensitive to changes in the concentration...	10.1038/nrmicro3508	This analysis proposes an elegant mechanism that can explain the robustness of two-component signalling against noise in gene expression.
10.1038/msb.2010.37	104,302,096	The Escherichia coli chemotaxis‐signaling pathway computes time derivatives of chemoeffector concentrations. This network features modules for signal reception/amplification and robust adaptation, with sensing of chemoeffector gradients determined by the way in which these modules are coupled in vivo . We characterized...	10.1038/nrmicro3508	This report demonstrates how FRET measurements of intracellular signal processing can be used to characterize the internal structure and dynamics of a network.
10.1073/pnas.0610561104	102,994,730	Amnesic patients have a well established deficit in remembering their past experiences. Surprisingly, however, the question as to whether such patients can imagine new experiences has not been formally addressed to our knowledge. We tested whether a group of amnesic patients with primary damage to the hippocampus bilat...	10.1038/nrn.2015.30	This paper shows that the hippocampus is critical for the ability to create episodic futures in humans.
10.1101/lm.031336.113	101,888,309	Learning by repetition engages distinct cognitive strategies whose contributions are adjusted with experience. Early in learning, performance relies upon flexible, attentive strategies. With extended practice, inflexible, automatic strategies emerge. This transition is thought fundamental to habit formation and applies...	10.1038/nrn.2015.30	On the classic Tolman–Hull plus maze, VTE arises with deliberative choices.
10.1073/pnas.1101328108	20,609,825	How do we make decisions when confronted with several alternatives (e.g., on a supermarket shelf)? Previous work has shown that accumulator models, such as the drift-diffusion model, can provide accurate descriptions of the psychometric data for binary value-based choices, and that the choice process is guided by visua...	10.1038/nrn.2015.30	Investigating human saccade–fixate–saccade sequences, this paper suggests a decision model and shows that it is consistent with the behavioural selections made by subjects.
10.1098/rstb.2013.0472	103,300,841	Both orbitofrontal cortex (OFC) and ventral striatum (vStr) have been identified as key structures that represent information about value in decision-making tasks. However, the dynamics of how this information is processed are not yet understood. We recorded ensembles of cells from OFC and vStr in rats engaged in the s...	10.1038/nrn.2015.30	In simultaneous recordings from the ventral striatum and the orbitofrontal cortex, ventral striatal representations show covert reward-related information before the turn-around during VTE, but orbitofrontal representations only show covert reward-related information after the turn-around point.
10.2337/dc13-0387	62,425,328	OBJECTIVE To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) techni...	10.1038/nrneph.2016.170	Treatment with the SGLT2 inhibitor dapagliflozin reduced both the maximum tubular reabsorptive capacity for glucose (Tm G ) and the renal threshold for glucosuria. From the clinical standpoint, the reduction in the renal threshold to <2.2 mmol/l (<40 mg/dl) is the primary mechanism responsible for the glucosuria and re...
10.2337/db13-0604	20,514,433	Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are a novel class of antidiabetes drugs, and members of this class are under various stages of clinical development for the management of type 2 diabetes mellitus (T2DM). It is widely accepted that SGLT2 is responsible for &gt;80% of the reabsorption of the renal...	10.1038/nrneph.2016.170	The amount of glucosuria induced by SGLT2 inhibitors is always less than expected based on the complete inhibition of SGLT2. This difference is explained by the ability of SGLT1 to markedly increase its reabsorption of glucose following SGLT2 inhibition.
10.1152/ajprenal.00518.2013	41,576,958	In the kidney, the sodium-glucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and ∼3% of fractional glucose reabsorption (FGR), respectively. However, euglycemic humans treated with an SGLT2 inhibitor maintain an FGR of 40–50%, mimicking values in Sglt2 knockout mice. Here, we show that oral gavage...	10.1038/nrneph.2016.170	This study demonstrated the important role of SGLT1 in glucose reabsorption following SGLT2 inhibition and explains why SGLT2 inhibitors never produce the expected amount of glucosuria even when with complete transporter inhibition.
10.2337/dc09-0517	109,098,234	OBJECTIVE To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS This was a randomized, double-blind, three-arm pa...	10.1038/nrneph.2016.170	Clinical study demonstrating the efficacy of add-on SGLT2 inhibitor therapy in patients with poorly controlled T2DM treated with insulin.
10.1210/jc.2014-3472	62,632,939	Abstract Background: β-Cell dysfunction is a core defect in T2DM, and chronic, sustained hyperglycemia has been implicated in progressive β-cell failure, ie, glucotoxicity. The aim of the present study was to examine the effect of lowering the plasma glucose concentration with dapagliflozin, a glucosuric agent, on β-ce...	10.1038/nrneph.2016.170	Clinical study in patients with T2DM demonstrating that treatment with an SGLT2 inhibitor induces glucosuria and reduces the plasma glucose concentration, leading to a marked improvement in β-cell function by ameliorating glucotoxicity.
10.2337/dc16-0041	62,275,970	Although cardiovascular (CV) mortality is the principal cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on CV disease (CVD) risk. Thus, novel strategies to reduce CVD risk in T2DM patients are needed. The recently published BI 10773 (Empagliflozin) ...	10.1038/nrneph.2016.170	Overview of the potential mechanisms by which SGLT2 inhibitors prevented cardiovascular events in the EMPA-REG OUTCOME Study.
10.2337/db16-0049	41,092,116	In clinical trials, a small increase in LDL cholesterol has been reported with sodium–glucose cotransporter 2 (SGLT2) inhibitors. The mechanisms by which the SGLT2 inhibitor empagliflozin increases LDL cholesterol levels were investigated in hamsters with diet-induced dyslipidemia. Compared with vehicle, empagliflozin ...	10.1038/nrneph.2016.170	This study provides a potential explanation as to why SGLT2 inhibitors cause a small rise in LDL cholesterol.
10.2337/dc16-0330	83,416,497	The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium–glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have ...	10.1038/nrneph.2016.170	Novel hypothesis suggesting that a switch in myocardial metabolism from glucose to ketones may reduce myocardial oxygen consumption and enhance myocardial contractility.
10.2337/dc15-0843	83,053,740	OBJECTIVE Sodium–glucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (euDKA) in hopes that it will enhance recognition of this potentially life-threatening complication. RESEARCH DESIGN AN...	10.1038/nrneph.2016.170	First report describing the development of diabetic ketoacidosis in diabetic patients treated with a SGLT2 inhibitor.
10.1111/j.1462-2920.2009.02071.x	125,040,141	Summary A bacterium in the genus Halomonas that grew on dimethylsulfoniopropionate (DMSP) or acrylate as sole carbon sources and that liberated the climate‐changing gas dimethyl sulfide in media containing DMSP was obtained from the phylloplane of the macroalga Ulva. We identified a cluster that contains genes specific...	10.1038/nrmicro2653	The first molecular genetics-based description of the genes and enzymes involved in an entire pathway for DMSP catabolism.
10.1126/science.1135370	81,597,929	Dimethyl sulfide (DMS) is a key compound in global sulfur and carbon cycles. DMS oxidation products cause cloud nucleation and may affect weather and climate. DMS is generated largely by bacterial catabolism of dimethylsulfoniopropionate (DMSP), a secondary metabolite made by marine algae. We demonstrate that the bacte...	10.1038/nrmicro2653	The first description of an enzyme, DddD, that cleaves DMSP to yield DMS.
10.1126/science.1130657	60,019,202	Flux of dimethylsulfide (DMS) from ocean surface waters is the predominant natural source of sulfur to the atmosphere and influences climate by aerosol formation. Marine bacterioplankton regulate sulfur flux by converting the precursor dimethylsulfoniopropionate (DMSP) either to DMS or to sulfur compounds that are not ...	10.1038/nrmicro2653	The characterization of dmdA , the first gene to be identified that is involved in DMSP catabolism, and which encodes DMSP demethylase in roseobacters and the SAR11 clade.
10.1126/science.277.5332.1684	83,409,602	In the developing nervous system, glial cells guide axons to their target areas, but it is unknown whether they help neurons to establish functional synaptic connections. The role of glial cells in synapse formation and function was studied in cultures of purified neurons from the rat central nervous system. In glia-fr...	10.1038/nrn3484	References 5 and 6 were the first studies to show that astrocytes can induce and control the number of excitatory synapses by secreting soluble signals.
10.1126/science.1222381	103,788,585	Born to Stay Together For as many neurons as there are in the brain, there are many more astrocytes. These backstage workers perform a variety of functions, such as sustaining the blood-brain barrier and providing a stabilized environment for neurons. Diversity of astrocyte function is reflected in different molecular ...	10.1038/nrn3484	The authors use genetic approaches to demonstrate that astrocytes are allocated to distinct spatial domains and that the ablation of specific astrocyte populations results in abnormal synaptogenesis.
10.1073/pnas.0914257107	82,423,723	Because mouse models play a crucial role in biomedical research related to the human nervous system, understanding the similarities and differences between mouse and human brain is of fundamental importance. Studies comparing transcription in human and mouse have come to varied conclusions, in part because of their rel...	10.1038/nrn3484	This study compares human and mouse transciptomes and finds that glial transciptomes might have evolutionarily diverged more than neuronal transcriptomes between these two species.
10.1146/annurev.neuro.22.1.567	83,270,314	▪ Abstract Human speech and birdsong have numerous parallels. Both humans and songbirds learn their complex vocalizations early in life, exhibiting a strong dependence on hearing the adults they will imitate, as well as themselves as they practice, and a waning of this dependence as they mature. Innate predispositions ...	10.1038/nrn1904	A detailed review of the many parallels between birdsong learning and the acquisition of speech in humans.
10.1126/science.7313697	123,921,510	Male canaries that have reached sexual maturity can, in subsequent years, learn new song repertoires. Two telencephalic song control nuclei, the hyperstriatum ventrale, pars caudale, and nucleus robustus archistriatalis are, respectively, 99 and 76 percent larger in the spring, when male canaries are producing stable a...	10.1038/nrn1904	The first demonstration that seasonal changes occur in the volume of nuclei in the song system of songbirds.
10.1002/cne.901650405	60,951,851	Abstract We have traced central nervous pathways controlling bird son in the canary using a combination of behavioral and anatomical techniques. Unilateral electrolytic brain lesions were made in adult male canaries whose son had been previously recorded and analysed on a sound spectrograph. After severral days of post...	10.1038/nrn1904	The first detailed study showing the involvement of nuclei in the 'song system' in birdsong.
10.1073/pnas.94.8.4097	122,094,628	There is increased neuronal firing in the high vocal center (a motor nucleus) and other song nuclei of canaries, Serinus canaria , and zebra finches, Taeniopygia guttata , whenever these songbirds sing or hear song. These observations suggested that song perception involved sensory and motor pathways. We now show that ...	10.1038/nrn1904	Shows a clear dissociation between song production (which involved increased neuronal activation in nuclei in the 'song system') and song perception (which involved increased neuronal activation in the NCM and CMM, but not the song system).
10.1073/pnas.89.15.6818	84,466,487	We investigated the participation of genomic regulatory events in the response of the songbird brain to a natural auditory stimulus of known physiological and behavioral relevance, birdsong. Using in situ hybridization, we detected a rapid increase in forebrain mRNA levels of an immediate-early gene encoding a transcri...	10.1038/nrn1904	The first study to apply the IEG technique to birdsong, showing that exposure of male zebra finches or canaries to conspecific song led to increased IEG expression in brain regions outside the conventional 'song system'.
10.1073/pnas.0510136103	19,849,707	In both humans and songbirds, infants learn vocalizations by imitating the sounds of adult tutors with whom they interact during an early sensitive period. Vocal learning occurs in few animal taxa; similarities in the imitation process between humans and songbirds make the songbird a unique system in which vocal learni...	10.1038/nrn1904	Electrophysiological demonstration of differential neuronal habituation to familiar and novel songs, correlated with the strength of song learning, that is consistent with earlier findings using expression of IEGs.
10.1002/cne.20118	82,387,746	Abstract The standard nomenclature that has been used for many telencephalic and related brainstem structures in birds is based on flawed assumptions of homology to mammals. In particular, the outdated terminology implies that most of the avian telencephalon is a hypertrophied basal ganglia, when it is now clear that m...	10.1038/nrn1904	A detailed proposal for a new nomenclature of the avian brain that makes it clear that there are important homologies between the brains of birds and mammals that were obscured by the old terminology.
10.1523/jneurosci.4022-09.2010	82,423,897	NMDA receptors (NMDARs) are critical mediators of activity-dependent synaptic plasticity, but the differential roles of NR2A- versus NR2B-containing NMDARs have been controversial. Here, we investigate the roles of NR2A and NR2B in long-term potentiation (LTP) in organotypic hippocampal slice cultures using RNA interfe...	10.1038/nrn3504	An interesting study that reconciles a highly controversial field by proposing that at mature synapses both, GluN2A and GluN2B subunits cooperate to induce LTP — GluN2A as part of the conducting channel and GluN2B as a structural scaffold for recruiting proteins that are important for LTP.
10.1126/science.1072873	20,607,154	N -methyl- d -aspartate receptors (NMDARs) mediate ischemic brain damage but also mediate essential neuronal excitation. To treat stroke without blocking NMDARs, we transduced neurons with peptides that disrupted the interaction of NMDARs with the postsynaptic density protein PSD-95. This procedure dissociated NMDARs f...	10.1038/nrn3504	This is the first paper to demonstrate that disrupting the interaction between GluN2B NMDARs and PSD95 reduces neuronal damage during ischaemia and improves neurological functions.
10.1126/science.1190287	104,341,626	Antidepressant Action of Ketamine In contrast to the weeks or months of treatment required for standard antidepressant medication, ketamine administration produces an antidepressant response within 4 to 6 hours in depressed patients. What lies behind the rapid actions of ketamine? Li et al. (p. 959 ; see the Perspectiv...	10.1038/nrn3504	In an effort to identify the cellular substrate underlying the rapid antidepressant effects of ketamine and GluN2B-selective antagonists, this work demonstrates that activation of the mammalian target of rapamycin (mTOR) pathway and the subsequent increase in new synapses are likely to be relevant events.
10.1085/jgp.39.1.87	109,185,846	The stretch receptor organs of Alexandrowicz in lobster and crayfish possess sensory neurons which have their cell bodies in the periphery. The cell bodies send dendrites into a fine nearby muscle strand and at the opposite pole they give rise to an axon running to the central nervous system. Mechanisms of excitation b...	10.1038/nrn919	An early review article that discusses inhibitory synaptic transmission. Written by one of the founders of the field.
10.1113/jphysiol.1988.sp017390	124,941,799	1. Pyramidal neurones from layers II and III of the rat primary somatosensory cortex and cat primary visual cortex were studied in vitro. Inhibitory postsynaptic potentials (IPSPs) and responses to exogenously applied gamma‐aminobutyric acid (GABA) and its analogue baclofen were characterized. The results from rats and...	10.1038/nrn919	A nice demonstration of biphasic GABA-mediated postsynaptic potentials in neocortical neurons. This study also illustrates that, when exogenous GABA is applied to different cell regions, a range of changes in membrane potential can be produced.
10.1523/jneurosci.16-20-06414.1996	81,658,004	Gramicidin perforated-patch-clamp recordings in brain slices were used to obtain an accurate assessment of the developmental change in the GABA A receptor reversal potential ( E GABA A ) in embryonic and early postnatal rat neocortical cells including neuroepithelial precursor cells, cortical plate neurons, and postnat...	10.1038/nrn919	Using the gramicidin-perforated-patch technique in brain slices, this study reveals a developmental shift in , which is dependent on changes in [Cl − i
10.1523/jneurosci.20-15-05764.2000	83,462,249	Recent studies have implicated the classical neurotransmitters GABA and glutamate in the regulation of neural progenitor proliferation. We now show that GABA and glutamate have opposite effects on the two neural progenitor populations in the ventricular zones (VZs) and subventricular zones (SVZs) of the embryonic cereb...	10.1038/nrn919	Experiments in slice culture indicating that GABA receptor activation differentially regulates precursor proliferation in cells of the VZ and the subventricular zone.
10.1523/jneurosci.19-23-10372.1999	19,247,329	We have performed a morphofunctional analysis of CA1 pyramidal neurons at birth to examine the sequence of formation of GABAergic and glutamatergic postsynaptic currents (PSCs) and to determine their relation to the dendritic arborization of pyramidal neurons. We report that at birth pyramidal neurons are heterogeneous...	10.1038/nrn919	A clear demonstration of the sequential formation of GABA and glutamate synapses in hippocampal neurons. Evidence is provided that GABA synapses are the first to form.
10.1152/jn.1991.65.2.247	41,136,074	1. The postnatal maturation of intracortical inhibitory circuitry and the development of responses to applied gamma-aminobutyric acid (GABA) and baclofen were studied in pyramidal and nonpyramidal neurons from layers II and III of the rat primary somatosensory and primary visual cortex, in vitro. 2. Depolarizing sponta...	10.1038/nrn919	A detailed study of the developmental changes in GABA-mediated synaptic signalling in neocortical neurons.
10.1113/jphysiol.1989.sp017762	26,871,747	1. Intracellular recordings were made from rat CA3 hippocampal neurones in vitro during the first eighteen days of postnatal life. The cells had resting membrane potentials more negative than ‐51 mV, action potentials greater than 55 mV and membrane input resistances of 117 +/‐ 12 M omega. An unusual characteristic of ...	10.1038/nrn919	Recordings from hippocampal neurons in early postnatal brain slices showing that GABA A -receptor-mediated synaptic transmission drives the production of giant membrane depolarizations. This finding led to the concept that GABA-mediated synaptic signalling is excitatory in the developing brain.
10.1113/jphysiol.1996.sp021505	102,191,975	1. Gramicidin‐perforated patch clamp recording was employed to study GABA‐mediated responses in rat hypothalamic neurones (n = 102) with an intracellular Cl‐ concentration unaltered by the pipette solution. 2. In young cultures after 1‐7 days in vitro (DIV), GABA induced depolarizing membrane potentials (+16.5 +/‐ 1.3 ...	10.1038/nrn919	Using the gramicidin-perforated-patch technique in cultured hypothalamic neurons, this study nicely illustrates the developmental shift in . This study also shows that GABA A receptor activation can directly excite developing neurons.
10.1242/dev.121.8.2327	62,233,022	gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the adult mammalian central nervous system. However, GABA depolarizes immature rat hippocampal neurons and increases intracellular Ca2+ ([Ca2+]i). Here we show, that GABA and the GABAA receptor agonist muscimol induce c-Fos immunoreactivity and ...	10.1038/nrn919	These two studies (references 155 and 156 ), which used cultured hippocampal neurons, indicate that GABA stimulation regulates BDNF expression, which, in turn, facilitates interneuron development. These effects are observed only early in culture, when GABA A receptor activation produces membrane depolarization and incr...
10.1073/pnas.1009076107	62,101,118	Phylogenetic threats such as spiders evoke our deepest primitive fears. When close or looming, such threats engage evolutionarily conserved monitoring systems and defense reactions that promote self-preservation. With the use of a modified behavioral approach task within functional MRI, we show that, as a tarantula was...	10.1038/nrn3524	Subjects were exposed to a live tarantula during fMRI scanning using a paradigm that allowed for the dissociation of brain regions responsive to absolute threat proximity versus approach and/or withdrawal of threat.
10.1126/science.1144161	41,755,752	All animals can predict the hedonic consequences of events they've experienced before. But humans can predict the hedonic consequences of events they've never experienced by simulating those events in their minds. Scientists are beginning to understand how the brain simulates future events, how it uses those simulation...	10.1038/nrn3524	The authors propose that decision-making about future events results from simulation of those events and their anticipated emotional consequences and discuss common errors of prospection that result from such simulations.
10.1126/science.1064437	20,253,796	One of the most dominant influences in the patterning of multicellular embryos is exerted by the Hedgehog (Hh) family of secreted signaling proteins. Here, we identify a segment polarity gene in Drosophila melanogaster , skinny hedgehog ( ski ), and show that its product is required in Hh-expressing cells for productio...	10.1038/nrn940	This study identified the palmitoyltransferase Ski, which catalyses the palmitoylation of hedgehog in the secretory pathway.
10.1042/bj3570625	59,088,735	The release of neurotransmitter at a synapse occurs via the regulated fusion of synaptic vesicles with the plasma membrane. The fusion of the two lipid bilayers is mediated by a protein complex that includes the plasma membrane target soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein (SNAP) rec...	10.1038/nrn940	This study showed that the palmitoylated cysteines of SNAP25 are required for efficient SNARE-complex dissociation and the regulation of vesicle exocytosis.
10.1083/jcb.126.2.353	28,204,136	Recent work has demonstrated that p56lck, a member of the Src family of protein tyrosine kinases (PTKs), is modified by palmitoylation of a cysteine residue(s) within the first 10 amino acids of the protein (in addition to amino-terminal myristoylation that is a common modification of the Src family of PTKs). This is n...	10.1038/nrn940	This study showed that palmitoylation is crucial for p59 fyn but not for p60 src partitioning into Triton-X-100-insoluble complexes that contain caveolae.
10.1042/bj3610663	102,103,568	Pulmonary surfactant protein C (SP-C) propeptide (proSP-C) is a type II transmembrane protein that is palmitoylated on two cysteines adjacent to its transmembrane domain. To study the structural requirements for palmitoylation of proSP-C, His-tagged human proSP-C and mutant forms were expressed in Chinese hamster ovary...	10.1038/nrn940	This work showed that the palmitoylation of surfactant protein C relies on specific sequence motifs and on the probability that the cysteine is in the vicinity of the membrane surface.
10.1083/jcb.200109059	20,579,210	The neural cell adhesion molecule (NCAM) has been reported to stimulate neuritogenesis either via nonreceptor tyrosine kinases or fibroblast growth factor (FGF) receptor. Here we show that lipid raft association of NCAM is crucial for activation of the nonreceptor tyrosine kinase pathway and induction of neurite outgro...	10.1038/nrn940	The authors showed that palmitoylation-dependent lipid raft association of NCAM is crucial for activation of the non-receptor tyrosine kinase pathway and the induction of neurite outgrowth.
10.1046/j.1471-4159.2001.00005.x	122,145,909	Although palmitoylation of the β 2 ‐adrenergic receptor (β 2 AR), as well as its phosphorylation by the cyclic AMP‐dependant protein kinase (PKA) and the β‐adrenergic receptor kinase (βARK), are known to play important roles in agonist‐promoted desensitization, their relative contribution and mutual regulatory influenc...	10.1038/nrn940	Depalmitoylation of the β 2 -adrenoceptor promotes receptor phosphorylation and receptor internalization.
10.1101/gad.10.24.3129	104,325,162	Identifying the signals that regulate stem cell differentiation is fundamental to understanding cellular diversity in the brain. In this paper we identify factors that act in an instructive fashion to direct the differentiation of multipotential stem cells derived from the embryonic central nervous system (CNS). CNS st...	10.1038/nrn2810	The authors established an in vitro system to culture NPCs and identified extracellular factors that direct lineage commitment, enabling analysis of the differentiation capacity of a given NPC.
10.1242/dev.01912	83,248,192	DNA methylation is a major epigenetic factor that has been postulated to regulate cell lineage differentiation. We report here that conditional gene deletion of the maintenance DNA methyltransferase I (Dnmt1) in neural progenitor cells (NPCs) results in DNA hypomethylation and precocious astroglial differentiation. The...	10.1038/nrn2810	References 69 and 71 showed that DNA methylation at gene regulatory elements of GFAP and JAK–STAT pathway components block astrocytic differentiation in early neocortical development.
10.1101/gad.309404	38,537,484	We showed previously that purified rat oligodendrocyte precursor cells (OPCs) can be induced by extracellular signals to convert to multipotent neural stem-like cells (NSLCs), which can then generate both neurons and glial cells. Because the conversion of precursor cells to stem-like cells is of both intellectual and p...	10.1038/nrn2810	References 100 and 101 showed that chromatin remodelling is involved in the reprogramming of lineage-committed oligodendrocytes into multipotent NPCs.
10.1073/pnas.012605299	125,069,579	Many forms of long-lasting behavioral and synaptic plasticity require the synthesis of new proteins. For example, long-term potentiation (LTP) that endures for more than an hour requires both transcription and translation. The signal-transduction mechanisms that couple synaptic events to protein translational machinery...	10.1038/nrn1557	The first study to show that mTOR is required for hippocampal synaptic plasticity.
10.1073/pnas.94.10.5395	38,578,223	Local translation of proteins in distal dendrites is thought to support synaptic structural plasticity. We have previously shown that metabotropic glutamate receptor (mGluR1) stimulation initiates a phosphorylation cascade, triggering rapid association of some mRNAs with translation machinery near synapses, and leading...	10.1038/nrn1557	Shows that stimulation of mGluRs results in the rapid translation of fragile X mental retardation protein near synapses.
10.1126/science.273.5280.1402	83,020,706	Two neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are able to produce a long-lasting enhancement of synaptic transmission in the hippocampus. Unlike other forms of plasticity, neurotrophin-induced plasticity exhibited an immediate requirement for protein synthesis. Plasticity...	10.1038/nrn1557	The first study to show that local protein synthesis is required for the potentiation of synpatic transmission in the hippocampus.
10.1126/science.288.5469.1254	38,241,381	A hippocampal pyramidal neuron receives more than 10 4 excitatory glutamatergic synapses. Many of these synapses contain the molecular machinery for messenger RNA translation, suggesting that the protein complement (and thus function) of each synapse can be regulated on the basis of activity. Here, local postsynaptic p...	10.1038/nrn1557	The first study to show that local protein synthesis is required for mGluR-LTD in the hippocampus.
10.1073/pnas.94.26.14770	122,147,725	N -methyl- d -aspartate receptor (NMDAR) activation has been implicated in forms of synaptic plasticity involving long-term changes in neuronal structure, function, or protein expression. Transcriptional alterations have been correlated with NMDAR-mediated synaptic plasticity, but the problem of rapidly targeting new p...	10.1038/nrn1557	This study, together with reference 125, shows that NMDA receptor activation regulates elongation factor 2 phosphorylation.
10.1126/science.1082609	84,352,363	Despite its implications for higher order functions of the brain, little is currently known about the molecular basis of left-right asymmetry of the brain. Here we report that synaptic distribution of N -methyl-D-aspartate (NMDA) receptor GluRϵ2 (NR2B) subunits in the adult mouse hippocampus is asymmetrical between the...	10.1038/nrn3371	References 11 and 12 provided a molecular basis for the structural and functional asymmetry of the hippocampus at the synaptic level.
10.1186/1749-8104-3-9	17,821,239	Abstract Background Functional lateralization is a conserved feature of the central nervous system (CNS). However, underlying left-right asymmetries within neural circuitry and the mechanisms by which they develop are poorly described. Results In this study, we use focal electroporation to examine the morphology and co...	10.1038/nrn3371	This study builds on results in references 61 and 62 to identify two subtypes of habenular projection neuron that are present in different ratios on the left and right and innervate different, non-overlapping regions of their target nucleus with morphologically distinct terminal arbors.
10.1111/j.1467-7687.2007.00659.x	29,269,116	Abstract The present study investigated whether facial expressions modulate visual attention in 7‐month‐old infants. First, infants’ looking duration to individually presented fearful, happy, and novel facial expressions was compared to looking duration to a control stimulus (scrambled face). The face with a novel expr...	10.1038/nrn2554	Provided evidence for adult-like emotion–attention interactions in infants and showed that the influence of fearful faces on attention in infants is not simply attributable to the novelty of these faces.
10.1111/j.1467-8624.2007.00994.x	41,721,076	To examine the ontogeny of emotional face processing, event‐related potentials (ERPs) were recorded from adults and 7‐month‐old infants while viewing pictures of fearful, happy, and neutral faces. Face‐sensitive ERPs at occipital–temporal scalp regions differentiated between fearful and neutral/happy faces in both adul...	10.1038/nrn2554	Reported evidence that affective significance modulates the early stages of cortical face processing in adults and 7-month-old infants.
10.1126/science.1070223	103,811,073	Between 6 and 10 months of age, the infant's ability to discriminate among native speech sounds improves, whereas the same ability to discriminate among foreign speech sounds decreases. Our study aimed to determine whether this perceptual narrowing is unique to language or might also apply to face processing. We tested...	10.1038/nrn2554	The first study to show that face-processing mechanisms are initially broadly tuned but narrow with experience.
10.1073/pnas.0406627102	20,714,941	Experience plays a crucial role for the normal development of many perceptual and cognitive functions, such as speech perception. For example, between 6 and 10 months of age, the infant's ability to discriminate among native speech sounds improves, whereas the ability to discriminate among foreign speech sounds decline...	10.1038/nrn2554	Demonstrated that one can rescue the sensitive period for discriminating monkey faces by providing infants with distributed exposure to monkey faces.
10.1073/pnas.142165999	101,725,834	A fundamental issue in human development concerns how the young infant's ability to recognize emotional signals is acquired through both biological programming and learning factors. This issue is extremely difficult to investigate because of the variety of sensory experiences to which humans are exposed immediately aft...	10.1038/nrn2554	Reported evidence of experience-dependent plasticity in brain networks underlying perception of universal facial expressions.
10.1073/pnas.2534856100	122,473,926	Caspase-1 plays a key role in inflammatory pathways by processing pro-IL-1β into the active cytokine mature IL-1β. Given its sequence similarity with the Caenorhabditis elegans cell death gene ced-3 ,it has long been speculated that caspase-1 may also play a role in cell death. However, an unequivocal role for caspase-...	10.1038/nrn3638	This study provides strong evidence for a caspase 1-dependent cell death pathway that is localized in neurons, using caspase 1-knockout mice.
10.1038/jcbfm.2009.46	83,184,336	Traumatic brain injury elicits acute inflammation that in turn exacerbates primary brain damage. A crucial part of innate immunity in the immune privileged central nervous system involves production of proinflammatory cytokines mediated by inflammasome signaling. Here, we show that the nucleotide-binding, leucine-rich ...	10.1038/nrn3638	One of several related studies to propose a novel role for NLRP1 activation in the response to acute brain injury.
10.4049/jimmunol.1100790	120,654,709	Abstract Streptococcus pneumoniae meningitis causes brain damage through inflammation-related pathways whose identity and mechanisms of action are yet unclear. We previously identified caspase-1, which activates precursor IL-1 type cytokines, as a central mediator of inflammation in pneumococcal meningitis. In this stu...	10.1038/nrn3638	This study shows that NLPR3 activation promotes brain injury in pneumococcal meningitis. This contrasts with pneumococcal pneumonia, in which NLRP3 inflammasome activation is protective.
10.1073/pnas.1002396107	125,207,597	ALS is a fatal motor neuron disease of adult onset. Neuroinflammation contributes to ALS disease progression; however, the inflammatory trigger remains unclear. We report that ALS–linked mutant superoxide dismutase 1 (SOD1) activates caspase-1 and IL-1β in microglia. Cytoplasmic accumulation of mutant SOD1 was sensed b...	10.1038/nrn3638	This study demonstrates that inflammasome activation in response to SOD1 enhances pathogenesis in an ALS model.
10.1210/en.2003-1504	83,295,421	Abstract Despite decades of research, we do not know the functional significance of most sex differences in the brain. We are heavily invested in the idea that sex differences in brain structure cause sex differences in behavior. We rarely consider the possibility that sex differences in brain structure may also preven...	10.1038/nrn1909	Excellent review of the evidence supporting an often underappreciated concept, namely, that sexual dimorphisms in the brain may exist to prevent, rather than create, sexual dimorphisms in behaviour.
10.1523/jneurosci.0357-05.2005	82,231,109	The morphology of the human cortex varies remarkably across individuals, regardless of overall brain size. It is currently unclear whether related cortical regions covary in gray matter density, as a result of mutually trophic influences or common experience-related plasticity. We acquired a structural magnetic resonan...	10.1038/nrn1909	Findings suggest that the amygdala is probably an especially important locus of sex influences on brain function.
10.1523/jneurosci.23-12-05329.2003	123,217,620	Relatively little is known about the basic mechanisms that play a role in the vulnerability of the developing brain toward adverse environmental influences. Our study in the South American rodent Octodon degus revealed that repeated brief separation from the parents and exposure to an unfamiliar environment induces in ...	10.1038/nrn1909	Demonstrates a qualitative difference in the neurochemical response to stress of an amygdala nucleus, the basomedial nucleus, not traditionally thought to be sexually dimorphic.
10.1126/science.7123240	123,062,493	Estrogen pellets were placed in either the right or left hypothalamus of newborn female rats so that only one side of this brain area was exposed to the postnatal masculinizing and defeminizing effects of the hormone. The effects of estrogen on gonadotropin secretion and reproductive behavior depended on both the regio...	10.1038/nrn1909	A striking demonstration of hemispheric lateralization in the effects of a sex hormone on the developing brain.
10.1210/en.2004-1142	45,562,715	Abstract Female and male brains differ. Differences begin early during development due to a combination of genetic and hormonal events and continue throughout the lifespan of an individual. Although researchers from a myriad of disciplines are beginning to appreciate the importance of considering sex differences in the...	10.1038/nrn1909	An excellent, comprehensive review by field leaders of various approaches taken to studying the issue of sex influences on the brain, including description of the pitfalls to be avoided. Should be mandatory reading for anyone entering the field.
10.1126/science.1110647	104,394,772	Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells...	10.1038/nrn2038	A crucial paper that uses novel in vivo technology to visualize the extensive vigilance of microglia, as they survey the brain environment.
10.1046/j.1471-4159.2002.00928.x	124,093,209	Abstract The etiology of sporadic Parkinson's disease (PD) remains unknown. Increasing evidence has suggested a role for inflammation in the brain in the pathogenesis of PD. However, it has not been clearly demonstrated whether microglial activation, the most integral part of the brain inflammatory process, will result...	10.1038/nrn2038	A crucial paper documenting that microglial activation is progressive and selective for dopaminergic neurons.
10.1073/pnas.0937239100	18,955,560	Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons, and can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both inflammatory processes and oxidative stress may co...	10.1038/nrn2038	A crucial paper illustrating the role of microglial NADPH oxidase in a component of MPTP-induced dopaminergic neurotoxicity.
10.3727/000000006783981990	18,924,499	Animal models have been an essential tool for researchers and clinicians in their efforts to study and treat Parkinson's disease (PD). Thus, the various ways 6-hydroxydopamine is employed, the use of MPTP in rodents and nonhuman primates, the prenatal exposure to bacterial endotoxin, the postnatal exposure to environme...	10.1038/nrn2038	An excellent review explaining the multiple hit hypothesis and how multiple cumulative environmental exposures are likely to result in neurodegenerative disease.
10.1146/annurev.neuro.22.1.197	103,818,825	▪ Abstract Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (...	10.1038/nrn1883	A comprehensive review of the cloning of monoamine oxidases, and the physiological and behavioural effects of their knockout.
10.1126/science.3875898	101,140,863	Monoclonal antibodies specific for monoamine oxidase (MAO) A and MAO B, respectively, were used to localize these enzymes in primate brain. The reagents recognized different populations of neurons: those that recognized MAO A were located in cell groups containing catecholamines, including the substantia nigra, nucleus...	10.1038/nrn1883	Describes the distribution of MAOs in primate brain at regional and cellular levels.
10.1126/science.8211186	41,561,421	Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted rape, and exhibitionism. Analysis of 24-hour urine samples indicate...	10.1038/nrn1883	Finds that a compulsive-aggressive phenotype results from lack of MAOA expression in humans.
10.1073/pnas.1833106100	102,369,817	One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiologica...	10.1038/nrn1883	Shows the possible association of low platelet MAO activity and smoking.
10.1073/pnas.0505975102	83,386,686	The three-dimensional structure of recombinant human monoamine oxidase A (hMAO A) as its clorgyline-inhibited adduct is described. Although the chain-fold of hMAO A is similar to that of rat MAO A and human MAO B (hMAO B), hMAO A is unique in that it crystallizes as a monomer and exhibits the solution hydrodynamic beha...	10.1038/nrn1883	Shows important differences between the active sites of rat and human MAOA.
10.1111/j.1471-4159.2005.03341.x	45,392,170	Abstract Several multifunctional iron chelators have been synthesized from hydroxyquinoline pharmacophore of the iron chelator, VK‐28, possessing the monoamine oxidase (MAO) and neuroprotective N ‐propargylamine moiety. They have iron chelating potency similar to desferal. M30 is a potent irreversible rat brain mitocho...	10.1038/nrn1883	Reports the potential value of a novel iron chelator and brain-selective irreversible MAOA/B inhibitor for treatment of neurodegenerative diseases.
10.1002/ana.410390106	40,851,883	Abstract In the controlled trial Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), 310 of the 800 enrolled subjects did not reach the primary end point of disability requiring levodopa therapy during 21 ± 4 (mean ± SD) months of observation or need early initiation of deprenyl (selegiline) during...	10.1038/nrn1883	Results of long-term studies showing l -deprenyl to be of short-term benefit during the early stages of Parkinson's disease.
10.1002/ana.410400116	40,846,723	Abstract Lazabemide (Ro 19‐6327) is a relatively short‐acting, reversible, and selective type B monoamine oxidase inhibitor that is not metabolized to amphetamines or other active compounds. We previously found lazabemide to be safe and well tolerated at dosages of up to 400 mg/day during a 6‐week study of 201 patients...	10.1038/nrn1883	The first successful clinical trial of the reversible MAOB inhibitor lazabemide in Parkinson's disease.
10.1111/j.1476-5381.1977.tb07506.x	58,205,533	1 Tranylcypromine (20 mg/kg) administration to rats totally inhibited brain monoamine oxidase (MAO) oxidation of 5‐hydroxytryptamine (5‐HT), phenylethylamine and dopamine as measured in vitro. When l ‐3,4‐dihydroxyphenylalanine ( l ‐DOPA) (50 mg/kg) was given 30 min after the tranylcypromine, brain dopamine and noradre...	10.1038/nrn1883	In vivo demonstration that dopamine is equally well metabolized by brain MAOA and MAOB in the rat.
10.1002/jnr.490300410	18,406,477	Abstract Deprenyl slows the progression of disabling symptoms in Parkinson's disease (PD) by an unknown mechanism. It can block the action of MPTP on substantia nigra compacta (SNc) neurons by inhibiting monoamine oxidase B necessary to mediate the conversion of MPTP to MPP+, its active metabolite, in astroglia. Mice w...	10.1038/nrn1883	Demonstration that l -deprenyl has 'neurorescue' activity when administered after neurons have been induced to degenerate.
10.1073/pnas.78.12.7639	81,447,438	Nucleotide sequences of the 3' 20% of the hemagglutinin gene of 32 influenza A virus strains from the 12 known hemagglutinin subtypes have been determined. Although the sequences of hemagglutinin genes and proteins of different subtypes differ greatly, cysteine and some other amino acid residues are totally conserved, ...	10.1038/nrmicro2613	A seminal study that has led to the current group and clade classification of influenza virus subtypes.
10.1126/science.1121586	19,487,967	The spread of H5N1 avian influenza viruses (AIVs) from China to Europe has raised global concern about their potential to infect humans and cause a pandemic. In spite of their substantial threat to human health, remarkably little AIV whole-genome information is available. We report here a preliminary analysis of the fi...	10.1038/nrmicro2613	The first comprehensive sequencing and genomic analysis of AIVs, leading to the identification of the NS1 PDZ domain-binding motif.
10.1126/science.1154137	20,574,778	Antigenic and genetic analysis of the hemagglutinin of â¼13,000 human influenza A (H3N2) viruses from six continents during 2002â2007 revealed that there was continuous circulation in east and Southeast Asia (E-SE Asia) via a region-wide network of temporally overlapping epidemics and that epidemics in the temperate...	10.1038/nrmicro2613	A genetic and antigenic analysis of human seasonal H3N2 viruses, demonstrating the dominant seeding characteristics of these viruses that originated from local epidemics in West and Southeast Asia.
10.1126/science.1122818	107,218,243	Most emerging infectious diseases in humans originate from animal reservoirs; to contain and eradicate these diseases we need to understand how and why some pathogens become capable of crossing host species barriers. Influenza virus illustrates the interaction of factors that limit the transmission and subsequent estab...	10.1038/nrmicro2613	An excellent review on the host, viral and environmental factors that affect and contribute to host tropism.
10.1126/science.1136212	103,749,846	The 1918 influenza pandemic was a catastrophic series of virus outbreaks that spread across the globe. Here, we show that only a modest change in the 1918 influenza hemagglutinin receptor binding site alters the transmissibility of this pandemic virus. Two amino acid mutations that cause a switch in receptor binding pr...	10.1038/nrmicro2613	The demonstration that the transmission of influenza A virus can be modulated by receptor-binding specificity.
10.1126/science.1124513	20,706,425	The hemagglutinin (HA) structure at 2.9 angstrom resolution, from a highly pathogenic Vietnamese H5N1 influenza virus, is more related to the 1918 and other human H1 HAs than to a 1997 duck H5 HA. Glycan microarray analysis of this Viet04 HA reveals an avian α2-3 sialic acid receptor binding preference. Introduction of...	10.1038/nrmicro2613	The first crystal structure of the HA of a HPAI virus.
10.1128/jvi.67.4.1761-1764.1993	61,135,956	The single gene reassortant virus that derives its PB2 gene from the avian influenza A/Mallard/NY/78 virus and remaining genes from the human influenza A/Los Angeles/2/87 virus exhibits a host range restriction (hr) phenotype characterized by efficient replication in avian tissue and failure to produce plaques in mamma...	10.1038/nrmicro2613	A seminal work which demonstrates that residue K627 of PB2 is an adaptation to the human host.
10.1126/science.1119392	62,427,515	The pandemic influenza virus of 1918–1919 killed an estimated 20 to 50 million people worldwide. With the recent availability of the complete 1918 influenza virus coding sequence, we used reverse genetics to generate an influenza virus bearing all eight gene segments of the pandemic virus to study the properties associ...	10.1038/nrmicro2613	The first study to describe the increased pathogenesis of the extinct 1918 pandemic H1N1 virus (reconstructed from plasmid DNA).
10.1099/vir.0.2008/004606-0	104,090,698	The non-structural (NS1) protein of influenza A viruses is a non-essential virulence factor that has multiple accessory functions during viral infection. In recent years, the major role ascribed to NS1 has been its inhibition of host immune responses, especially the limitation of both interferon (IFN) production and th...	10.1038/nrmicro2613	A thorough review discussing the many functions and properties of the NS1 protein of influenza viruses.
10.1073/pnas.0914994107	81,985,247	Influenza A virus is being extensively studied because of its major impact on human and animal health. However, the dynamics of influenza virus infection and the cell types infected in vivo are poorly understood. These characteristics are challenging to determine, partly because there is no efficient replication-compet...	10.1038/nrmicro2613	The demonstration that natural killer cells, B cells and antigen-presenting cells, in addition to epithelial cells, are susceptible to influenza A virus infection in vivo
10.1073/pnas.1001984107	103,332,707	The discovery of regulatory small RNAs continues to reshape paradigms in both molecular biology and virology. Here we describe examples of influenza A virus-derived small viral RNAs (svRNAs). svRNAs are 22–27 nt in length and correspond to the 5′ end of each of the viral genomic RNA (vRNA) segments. Expression of svRNA...	10.1038/nrmicro2613	A study showing the generation and accumulation of a small viral RNA that seems to regulate the switch from transcription to replication in influenza viruses during infection.
10.1186/1471-2164-10-104	107,215,823	Abstract Background The availability of hundreds of bacterial genomes allowed a comparative genomic study of the Type VI Secretion System (T6SS), recently discovered as being involved in pathogenesis. By combining comparative and phylogenetic approaches using more than 500 prokaryotic genomes, we characterized the glob...	10.1038/nrmicro3185	This paper provides an exhaustive analysis of the distribution and gene content of T6S clusters.
10.1073/pnas.1213963109	20,700,611	Interbacterial interaction pathways play an important role in defining the structure and complexity of bacterial associations. A quantitative description of such pathways offers promise for understanding the forces that contribute to community composition. We developed time-lapse fluorescence microscopy methods for qua...	10.1038/nrmicro3185	This was the first study to show that inactivation of T6S can provide resistance to T6S-based attack by neighbouring cells.
10.1128/mmbr.00036-06	83,496,887	SUMMARY Colicins are proteins produced by and toxic for some strains of Escherichia coli . They are produced by strains of E. coli carrying a colicinogenic plasmid that bears the genetic determinants for colicin synthesis, immunity, and release. Insights gained into each fundamental aspect of their biology are presente...	10.1038/nrmicro3185	This is a comprehensive review of colicins, which are the best characterized of the bacteriocins.

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