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10.1073/pnas.0404200101 | 62,327,934 | The bacterium Caulobacter crescentus divides asymmetrically as part of its normal life cycle. This asymmetry is regulated in part by the membrane-bound histidine kinase PleC, which localizes to one pole of the cell at specific times in the cell cycle. Here, we track single copies of PleC labeled with enhanced yellow fl... | 10.1038/nrmicro3154 | This paper provides the first evidence that single copies of fluorescent protein fusions can be imaged and analysed in bacteria. |
10.1126/science.1175685 | 18,452,075 | Despite their small size, bacteria have a remarkably intricate internal organization. Bacteria deploy proteins and protein complexes to particular locations and do so in a dynamic manner in lockstep with the organized deployment of their chromosome. The dynamic subcellular localization of protein complexes is an integr... | 10.1038/nrmicro3154 | This review describes the central role that protein localization patterns have in bacterial cell biology, which should be investigated using advanced imaging methods. |
10.1073/pnas.0604503103 | 58,375,710 | The actin cytoskeleton represents a key regulator of multiple essential cellular functions in both eukaryotes and prokaryotes. In eukaryotes, these functions depend on the orchestrated dynamics of actin filament assembly and disassembly. However, the dynamics of the bacterial actin homolog MreB have yet to be examined ... | 10.1038/nrmicro3154 | This study shows that single copies of MreB move in a slow, directed, circumferential fashion around the cell periphery in C. crescentus |
10.1126/science.1227126 | 20,828,629 | Making a Move Structural Maintenance of Chromosome (SMC) complexes act ubiquitously in chromosome processing in all domains of life, but their mode of action in living cells has remained an enigma. Badrinarayanan et al. (p. 528 ) used noninvasive millisecond single-molecule imaging to understand SMC complex molecular b... | 10.1038/nrmicro3154 | This paper determines the minimal functional complex of MukBEF in living cells using single-molecule imaging and stoichimetry analysis. |
10.1126/science.1119623 | 19,598,880 | We directly observed real-time production of single protein molecules in individual Escherichia coli cells. A fusion protein of a fast-maturing yellow fluorescent protein (YFP) and a membrane-targeting peptide was expressed under a repressed condition. The membrane-localized YFP can be detected with single-molecule sen... | 10.1038/nrmicro3154 | This paper uses single-molecule imaging to directly observe gene expression dynamics in live cells. |
10.1242/jcs.123612 | 39,808,217 | Summary Super-resolution fluorescence imaging by single-molecule photoactivation or photoswitching and position determination (localization microscopy) has the potential to fundamentally revolutionize our understanding of how cellular function is encoded at the molecular level. Among all powerful, high-resolution imagi... | 10.1038/nrmicro3154 | This paper provides a comprehensive review of single-molecule localization microscopy, with a thorough discussion of current challenges. |
10.1146/annurev.micro.091208.073158 | 102,625,327 | Cooperation is integral to much of biological life but can be threatened by selfish evolutionary strategies. Diverse cooperative traits have evolved among microbes, but particularly sophisticated forms of sociality have arisen in the myxobacteria, including group motility and multicellular fruiting body development. My... | 10.1038/nrmicro2750 | A review describing the ease of the evolution (back and forth) of social behavioural traits. |
10.1073/pnas.0911253107 | 61,507,939 | Specific small deletions within the rpoC gene encoding the β′-subunit of RNA polymerase (RNAP) are found repeatedly after adaptation of Escherichia coli K-12 MG1655 to growth in minimal media. Here we present a multiscale analysis of these mutations. At the physiological level, the mutants grow 60% faster than the pare... | 10.1038/nrmicro2750 | An example of evolution towards new kinetic properties of the transcriptional machinery to confer higher fitness in minimal media. |
10.1073/pnas.0803151105 | 20,428,467 | The role of historical contingency in evolution has been much debated, but rarely tested. Twelve initially identical populations of Escherichia coli were founded in 1988 to investigate this issue. They have since evolved in a glucose-limited medium that also contains citrate, which E. coli cannot use as a carbon source... | 10.1038/nrmicro2750 | A seminal evolution replay experiment demonstrating the emergence of a phenotypic innovation that transcends the species boundaries through historical contingency. |
10.1126/science.1198914 | 62,127,617 | Descendants of bacterial lineages that retained adaptation potential outcompeted competitors of higher fitness. | 10.1038/nrmicro2750 | The demonstration that beneficial alleles can be selected because of their future evolvability. |
10.1073/pnas.0608018103 | 20,783,724 | Extracellular proton concentrations in the brain may be an important signal for neuron function. Proton concentrations change both acutely when synaptic vesicles release their acidic contents into the synaptic cleft and chronically during ischemia and seizures. However, the brain receptors that detect protons and their... | 10.1038/nrn3529 | The authors of this study detected ASIC1A in dendritic spines and implicated it in synaptic plasticity. |
10.1073/pnas.1205902109 | 61,422,218 | Localized pH changes have been suggested to occur in the brain during normal function. However, the existence of such pH changes has also been questioned. Lack of methods for noninvasively measuring pH with high spatial and temporal resolution has limited insight into this issue. Here we report that a magnetic resonanc... | 10.1038/nrn3529 | This study shows that brain activation produces a functional acidosis that is detectable with MRI. |
10.1523/jneurosci.23-19-07351.2003 | 17,251,940 | The factors governing the characteristic laminated termination of hippocampal afferents are essentially unknown. Principally, diffusible factors of the target region, membrane-bound molecules on the ingrowing afferent fibers and on the postsynaptic target cells as well as molecules of the extracellular matrix (ECM), ma... | 10.1038/nrn1882 | By using co-cultures of wild-type and mutant hippocampus this paper shows that components of the ECM control the lamination of entorhinal fibres to the dentate gyrus. By contrast, positional cues on the target cells guide commissural/associational fibres. |
10.1242/dev.129.18.4249 | 20,808,872 | The dentate gyrus is the primary afferent pathway into the hippocampus, but there is little information concerning the molecular influences that govern its formation. In particular, the control of migration and cell positioning of dentate granule cells is not clear. We have characterized more fully the timing and route... | 10.1038/nrn1882 | Characterizes the route of migration of dentate granule cells using in utero retroviral injections. Moreover, the chemokine SDF1 and its receptor CXCR4 were found to regulate granule cell migration. |
10.1242/dev.01387 | 104,233,547 | Reelin is required for the proper positioning of neurons in the cerebral cortex. In the reeler mutant lacking reelin, the granule cells of the dentate gyrus fail to form a regular, densely packed cell layer. Recent evidence suggests that this defect is due to the malformation of radial glial processes required for gran... | 10.1038/nrn1882 | When a slice of reeler hippocampus was co-cultured to a wild-type hippocampal slice the lamination of dentate granule cells was rescued in the reeler slice, showing that reelin needs to be in a specific location to exert its effect on granule cell lamination. |
10.1126/science.287.5454.864 | 62,191,077 | Brain function requires precisely orchestrated connectivity between neurons. Establishment of these connections is believed to require signals secreted from outgrowing axons, followed by synapse formation between selected neurons. Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmit... | 10.1038/nrn1882 | Despite the lack of transmitter release in Munc18-1-deficient mice, cortical layers, fibre projections and synaptic structures develop normally. |
10.1523/jneurosci.22-14-05797.2002 | 124,160,574 | The reelin signaling pathway plays a crucial role during the development of laminated structures in the mammalian brain. Reelin, which is synthesized and secreted by Cajal–Retzius cells in the marginal zone of the neocortex and hippocampus, is proposed to act as a stop signal for migrating neurons. Here we show that a ... | 10.1038/nrn1882 | The extent of granule cell dispersion in patients with epilepsy was found to correlate with a loss of reelin-synthesizing Cajal–Retzius cells, indicating that reelin could have a role in the maintenance of granule cell lamination in the adult human brain. |
10.1523/jneurosci.3648-05.2006 | 82,941,291 | Adult neurogenesis in the dentate gyrus may contribute to hippocampus-dependent functions, yet little is known about when and how newborn neurons are functional because of limited information about the time course of their connectivity. By using retrovirus-mediated gene transduction, we followed the dendritic and axona... | 10.1038/nrn1882 | The authors used retrovirus-mediated gene transduction to monitor the dendritic and axonal differentiation of adult-born dentate granule cells. |
10.1126/science.271.5254.1423 | 122,978,450 | Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25 , was identified in the critical region for the FRDA locus on chromosome 9q13. The gene encodes a 210-amino acid protein, frataxin, that has homologs in distant ... | 10.1038/nrn1474 | Cloning of the Friedreich ataxia gene and identification of a novel genetic mechanism of disease consisting of the expansion of a GAA triplet in an intron of a recessive gene. |
10.1038/sj.embor.embor918 | 100,847,465 | Depletion of the mitochondrial matrix protein frataxin is the molecular cause of the neurodegenerative disease Friedreich ataxia. The function of frataxin is unclear, although recent studies have suggested a function of frataxin (yeast Yfh1) in iron/sulphur (Fe/S) protein biogenesis. Here, we show that Yfh1 specificall... | 10.1038/nrn1474 | One of the most convincing demonstrations that frataxin is involved in the biogenesis of Fe–S clusters by showing its specific interaction with a protein that is crucial in the early steps of Fe–S centre biosynthesis. |
10.1084/jem.20041679 | 82,982,843 | Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease... | 10.1038/nrneurol.2017.81 | First demonstration of so-called immune resetting; a new and more diverse T cell repertoire is regenerated following thymus reactivation post-transplantation, leading to increase of naive T cells. |
10.1002/ana.23784 | 103,755,973 | Objective To define changes in phenotype and functional responses of reconstituting T cells in patients with aggressive multiple sclerosis (MS) treated with ablative chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). Methods Clinical and brain magnetic resonance imaging measures of disease acti... | 10.1038/nrneurol.2017.81 | Study of T cells from successfully treated patients demonstrated that they have a reduced proinflammatory interleukin-17 response after transplantation. |
10.1152/physrev.1995.75.4.689 | 62,228,158 | Nonsynaptic interactions between neurons have been eclipsed by our increasingly detailed understanding of chemical synapses, but they do play significant roles in the nervous system. This review considers four classes of nonsynaptic interaction, mainly in mammalian brain. 1) Electrotonic (and chemical) coupling through... | 10.1038/nrn3241 | The most comprehensive text on the ephaptic effects in the brain to date. |
10.1152/jn.00979.2005 | 83,290,096 | Although extracellular unit recording is typically used for the detection of spike occurrences, it also has the theoretical ability to report about what are typically considered intracellular features of the action potential. We address this theoretical ability by developing a model system that captures features of exp... | 10.1038/nrn3241 | The first simultaneous intra- and extracellular modelling of action potentials. |
10.1152/jn.1975.38.2.356 | 104,033,035 | The theoretical basis of current source-density (CSD) analysis in the central nervous system is described. Equations relating CSD, the current flow vector, and the extracellular field potential are given. It is shown that the CSD provides superior resolution of neuronal events when compared to conventional field-potent... | 10.1038/nrn3241 | A pioneering study of the physical basis of the extracellular currents. |
10.1126/science.11560 | 88,222,676 | Sensitization is an elementary form of nonassociative learning, related to behavioral arousal, in which a strong stimulus facilitates a reflex response. Studies of the neural circuit of the gill-withdrawal reflex in the isolated abdominal ganglion of Aplysia indicate that short-term sensitization is due to presynaptic ... | 10.1038/nrn2117 | Study of the neural circuit of the gill-withdrawal reflex in the isolated abdominal ganglion of Aplysia , indicating that short-term sensitization is due to presynaptic facilitation. |
10.1126/science.280.5360.69 | 83,368,665 | The potassium channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K + channels, particularly in the pore region. X-ray analysis with data to 3.2 angstroms reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the ... | 10.1038/nrn2117 | Uses x-ray analysis to reveal that four identical KcsA subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. |
10.1073/pnas.71.11.4457 | 101,187,042 | We propose that membranes whose proteins and polar lipids are distributed asymmetrically in the two halves of the membrane bilayer can act as bilayer couples, i.e., the two halves can respond differently to a perturbation. This hypothesis is applied to the interactions of amphipathic drugs with human erythrocytes. It i... | 10.1038/nrn2117 | Shows that membranes whose polar lipids are distributed asymmetrically in the two halves of the membrane bilayer can act as bilayer couples, that is, the two halves can respond differently to a perturbation. This hypothesis is applied to the interactions of amphipathic drugs with human erythrocytes. |
10.1002/med.10035 | 100,607,622 | Abstract The bicyclic furo[2,3‐ d ]pyrimidine nucleoside analogues represent an entirely new class of fused furopyrimidine derivatives with unprecedented selectivity for varicella‐zoster virus (VZV). From extensive structure‐activity relationship (SAR) studies, the 6‐( p ‐alkylphenyl)substituted furopyrimidine derivati... | 10.1038/nrmicro975 | References 12 and 13, reviewed in reference 14, describe a new class of nucleoside analogues with unprecedented high potency as antiviral agents. |
10.1073/pnas.0905966106 | 36,474,916 | Infection with the hepatitis C virus (HCV) has a huge impact on global health putting more than 170 million people at risk of developing severe liver disease. The HCV encoded p7 ion channel is essential for the production of infectious viruses. Despite a growing body of functional data, little is known about the 3-dime... | 10.1038/nrmicro2820 | This article provides the first reported structural reconstruction of a full-length viroporin immersed in a membrane-like environment. |
10.1073/pnas.1007071107 | 58,440,151 | The M2 proton channel from influenza A virus is an essential protein that mediates transport of protons across the viral envelope. This protein has a single transmembrane helix, which tetramerizes into the active channel. At the heart of the conduction mechanism is the exchange of protons between the His37 imidazole mo... | 10.1038/nrmicro2820 | On the basis of the high-resolution structure of the M2 channel, the authors of this report suggest mechanisms for proton conductance and asymmetrical diffusion in the presence of a proton gradient. |
10.1073/pnas.1000081107 | 125,323,192 | The colonization process of the infant gut microbiome has been called chaotic, but this view could reflect insufficient documentation of the factors affecting the microbiome. We performed a 2.5-y case study of the assembly of the human infant gut microbiome, to relate life events to microbiome composition and function.... | 10.1038/nrmicro2540 | A pilot study describing the colonization process of the infant gut microbiome from birth to 2.5 years of age; this study reveals that seemingly chaotic shifts in the microbiome are explained by events in the infant's life, such as diet change, antibiotic treatment and others. |
10.1126/science.1179721 | 38,251,965 | Debugging Metabolic Disease Obesity, now officially recognized as an epidemic in many developed nations, is a key component of “metabolic syndrome,” an array of metabolic disturbances that increase an individual's risk of developing diabetes and heart disease. The rise in obesity rates has been largely attributed to th... | 10.1038/nrmicro2540 | This article shows that TLR5 deficiency in mice results in an altered microbiota that is associated with metabolic syndrome. Transplanting this altered microbiome confers the disease state to germ-free recipient wild-type mice. |
10.1073/pnas.1007028107 | 125,307,652 | In vertebrates, including humans, individuals harbor gut microbial communities whose species composition and relative proportions of dominant microbial groups are tremendously varied. Although external and stochastic factors clearly contribute to the individuality of the microbiota, the fundamental principles dictating... | 10.1038/nrmicro2540 | The first study taking a QTL-based approach to relate genomic variation in the host to microbial diversity in the gut. Testing of the CMM abundances for co-segregation with 530 SNPs identifies 18 host-associated QTLs that show a linkage with the abundances of specific microbial taxa. |
10.1073/pnas.1000099107 | 19,444,108 | Vertebrates engage in symbiotic associations with vast and complex microbial communities that colonize their gastrointestinal tracts. Recent advances have provided mechanistic insight into the important contributions of the gut microbiome to vertebrate biology, but questions remain about the evolutionary processes that... | 10.1038/nrmicro2540 | A study describing the evolutionary processes that shape the symbiotic interactions between microorganisms and the host gut, focusing on Lactobacillus reuteri |
10.1126/science.1123511 | 20,833,246 | Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phas... | 10.1038/nrn1971 | Elegantly highlights the importance of microglia for disease progression in transgenic ALS mice. |
10.1126/science.1086137 | 103,321,245 | Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neuromuscular disease that is associated with the degeneration of spinal and brainstem motor neurons, leading to atrophy of limb, axial, and respiratory muscles. The cause of ALS is unknown, and there is no effective therapy. Neurotrophic factors are candidat... | 10.1038/nrn1971 | Describes an effective therapy in ALS mice based on the delivery of insulin-like growth factor 1 (IGF1) to motor neurons via a retrogradely transported AAV2–IGF1 gene therapy vector. |
10.1002/syn.890060306 | 40,032,916 | Abstract The manner in which the circuitry of the amygdala computes its suspected mnemonic has been a mystery, partly cellular analysis. Here we report in vitro methods and results that may help elucidate cellular learning mechanisms in amygdala neurons. The amygdala brain slice preparation was combined with the single... | 10.1038/nrn1535 | A seminal paper that demonstrated for the first time that amygdala neurons show long-term synaptic potentiation in vitro |
10.1101/lm.30901 | 84,385,131 | Fear conditioning is a form of associative learning in which subjects come to express defense responses to a neutral conditioned stimulus (CS) that is paired with an aversive unconditioned stimulus (US). Considerable evidence suggests that critical neural changes mediating the CS–US association occur in the lateral nuc... | 10.1038/nrn1535 | An excellent review covering the cellular and synaptic mechanisms in the lateral amygdala that underlie the acquisition of long-term fear memories. |
10.1146/annurev.physiol.66.082602.092845 | 83,502,316 | ▪ Abstract The development of functional magnetic resonance imaging (fMRI) has brought together a broad community of scientists interested in measuring the neural basis of the human mind. Because fMRI signals are an indirect measure of neural activity, interpreting these signals to make deductions about the nervous sys... | 10.1038/nrn2154 | This paper reviews the relationship between neural activity and the fMRI BOLD signal. A key conclusion is that the BOLD response can depend nonlinearly on the neural signal and that this nonlinearity can differ across brain regions. |
10.1126/science.1121449 | 61,635,680 | During development, cells monitor and adjust their rates of accumulation to produce organs of predetermined size. We show here that central nervous system–specific deletion of the essential adherens junction gene, α E-catenin, causes abnormal activation of the hedgehog pathway, resulting in shortening of the cell cycle... | 10.1038/nrn2058 | Along with reference 120, this paper shows a crucial role for adherens junction signalling in the regulation of cell proliferation and neurogenesis in the embryonic mammalian brain. |
10.1073/pnas.93.26.15435 | 21,679,731 | Pain differs from other sensations in many respects. Primary pain-sensitive neurons respond to a wide variety of noxious stimuli, in contrast to the relatively specific responses characteristic of other sensory systems, and the response is often observed to sensitize on repeated presentation of a painful stimulus, whil... | 10.1038/nrn1141 | Shows that the cell bodies of DRG neurons can be used to study some properties of nociception that had previously been reported in pain-sensitive nerve terminals, and that the response to noxious heat that was observed in these cells was due to an ion channel. |
10.1113/jphysiol.1969.sp008820 | 104,309,376 | 1. A detailed theory of cerebellar cortex is proposed whose consequence is that the cerebellum learns to perform motor skills. Two forms of input—output relation are described, both consistent with the cortical theory. One is suitable for learning movements (actions), and the other for learning to maintain posture and ... | 10.1038/nrn1953 | Contains some of the most influential theoretical ideas related to cerebellar information processing. |
10.1523/jneurosci.17-01-00438.1997 | 19,247,253 | In our ongoing attempt to determine the anatomic substrates that could support a cerebellar contribution to cognitive processing, we investigated the prefrontal cortical projections to the basilar pons. A detailed understanding of these pathways is needed, because the prefrontal cortex is critical for a number of compl... | 10.1038/nrn1953 | The authors have characterized patterns of projections from several prefrontal areas to the pontine nuclei. |
10.1523/jneurosci.23-23-08432.2003 | 41,745,371 | We used transneuronal transport of neurotropic viruses to examine the topographic organization of circuits linking the cerebellar cortex with the arm area of the primary motor cortex (M1) and with area 46 in dorsolateral prefrontal cortex of monkeys. Retrograde transneuronal transport of the CVS-11 (challenge virus str... | 10.1038/nrn1953 | The only study in the literature so far that has identified the trans-synaptic pathways from motor and prefrontal areas to distinct locations in the cerebellar cortex in the primate brain. The importance of this study lies in the fact that it allows researchers to generate anatomically specific hypotheses about the ope... |
10.1126/science.1212003 | 41,756,036 | Even the adult primary visual cortex is sufficiently plastic to allow performance enhancement. | 10.1038/nrn.2016.164 | This was the first study with real-time fMRI-based neurofeedback demonstrating that the adult primate early visual cortex is plastic enough for visual perceptual learning. |
10.1162/jocn_a_00802 | 60,443,040 | Real-time fMRI (rtfMRI) neurofeedback (NF) facilitates volitional control over brain activity and the modulation of associated mental functions. The NF signals of traditional rtfMRI-NF studies predominantly reflect neuronal activity within ROIs. In this study, we describe a novel rtfMRI-NF approach that includes a func... | 10.1038/nrn.2016.164 | This study showed the importance of how inclusion of functional connectivity information in the feedback signal improves self-regulation learning and behavioural outcome. |
10.1177/1545968310385128 | 85,620,864 | Background. Studies with real-time functional magnetic resonance imaging (fMRI) demonstrate that humans volitionally regulate hemodynamic signals from circumscribed regions of the brain, leading to area-specific behavioral consequences. Methods to better determine the nature of dynamic functional interactions between d... | 10.1038/nrn.2016.164 | This study showed the change in connectivity pattern of the brain due to learned volitional control of a circumscribed brain area. |
10.1126/science.163.3870.955 | 81,832,852 | The activity of single neurons in precentral cortex of unanesthetized monkeys ( Macaca mulatta ) was conditioned by reinforcing high rates of neuronal discharge with delivery of a food pellet. Auditory or visual feedback of unit firing rates was usually provided in addition to food reinforcement. After several training... | 10.1038/nrn.2016.164 | This was the first study to demonstrate the feasibility of realizing volitional control of a single neuron by operant training. |
10.1002/hbm.23228 | 103,996,955 | Abstract The learning process involved in achieving brain self‐regulation is presumed to be related to several factors, such as type of feedback, reward, mental imagery, duration of training, among others. Explicitly instructing participants to use mental imagery and monetary reward are common practices in real‐time fM... | 10.1038/nrn.2016.164 | This study investigated several factors (for example, reward, instruction and feedback) that influence the learning process during neurofeedback training, showing that participants who are trained with visual feedback without explicit instruction for using mental imagery show an increase in BOLD self-regulation compare... |
10.1073/pnas.1516857113 | 125,050,973 | Recent advances in blood oxygen level-dependent–functional MRI (BOLD-fMRI)-based neurofeedback reveal that participants can modulate neuronal properties. However, it is unknown whether such training effects can be introduced in the absence of participants' awareness that they are being trained. Here, we show unconsciou... | 10.1038/nrn.2016.164 | This study demonstrated that volitional control of brain activations could be learned when participants were unaware that they were undergoing neurofeedback training and did not have any explicit awareness of the feedback signal. |
10.1002/ana.23879 | 62,174,600 | Objective Chronic stroke patients with severe hand weakness respond poorly to rehabilitation efforts. Here, we evaluated efficacy of daily brain–machine interface (BMI) training to increase the hypothesized beneficial effects of physiotherapy alone in patients with severe paresis in a double‐blind sham‐controlled desig... | 10.1038/nrn.2016.164 | This study provided haptic feedback in a BCI training paradigm, demonstrating improvement in motor function in patients with chronic stroke. |
10.1126/science.6823561 | 83,531,158 | Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking pa... | 10.1038/nrn1868 | The first major study to show that MPTP can induce parkinsonism in humans. |
10.1126/science.276.5321.2045 | 83,454,674 | Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromoso... | 10.1038/nrn1868 | The first report of a single gene mutation resulting in PD. |
10.1126/science.1063522 | 103,236,645 | The substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily α-synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and α-synuclein fibrilization. All but one of 15 fibril inhibito... | 10.1038/nrn1868 | An important paper showing that dopamine modulates α-synuclein aggregation, which suggests a mechanism for the regional selectivity of PD. |
10.1126/science.1096284 | 20,852,060 | Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have ... | 10.1038/nrn1868 | The first report of a PD gene unequivocally localized to mitochondria. |
10.1126/science.2937147 | 104,149,216 | Human color vision is based on three light-sensitive pigments. The isolation and sequencing of genomic and complementary DNA clones that encode the apoproteins of these three pigments are described. The deduced amino acid sequences show 41 ± 1 percent identity with rhodopsin. The red and green pigments show 96 percent ... | 10.1038/nrn2880 | Together with another paper in the same issue of Science , Nathans and colleagues establish the fundamental basis for colour vision and associated inherited variations in humans. |
10.1002/cne.901880205 | 100,358,813 | Abstract The period of cell genesis of rod and cone photoreceptor cells has been determined in the retinas of C57BL/6J mice. Embryonic mice were exposed to a single dose of 3 H‐thymidine at embryonic day (E) 10‐18 by injecting pregnant mice intraperitoneally. Animals at postnatal ages were injected subcutaneously once ... | 10.1038/nrn2880 | An elegant delineation of the period of rod and cone photoreceptor genesis in the mouse retina, validated over 25 years later by studies on Nrl and Thrb as specific genetic markers of newly generated rods and cones, respectively. |
10.1126/science.2911751 | 60,486,045 | The relation between terminal mitosis and the events that determine the developmental fate of embryonic precursor cells is not well understood. This relation has now been investigated with [ 3 H]thymidine autoradiography to determine the time of cell birth and with a culture system that allows the testing of the develo... | 10.1038/nrn2880 | An early demonstration of developmental plasticity in post-mitotic cells in the chick embryo retina. |
10.1073/pnas.93.2.589 | 62,436,923 | In the vertebrate central nervous system, the retina has been a useful model for studies of cell fate determination. Recent results from studies conducted in vitro and in vivo suggest a model of retinal development in which both the progenitor cells and the environment change over time. The model is based upon the noti... | 10.1038/nrn2880 | A comprehensive model that helped to integrate the diverse experimental observations on lineage and cell fate determination in the developing retina. |
10.1073/pnas.0605934104 | 42,580,038 | Networks of transcriptional regulatory proteins dictate specification of neural lineages from multipotent retinal progenitors. Rod photoreceptor differentiation requires the basic motif–leucine zipper (bZIP) transcription factor NRL, because loss of Nrl in mice ( Nrl −/− ) results in complete transformation of rods to ... | 10.1038/nrn2880 | Refs 57 and 58 are key papers that demonstrated and established the essential and instructive role of NRL in photoreceptor differentiation. |
10.1073/pnas.0902425106 | 16,807,988 | Rods and cones are morphologically and developmentally distinct photoreceptor types with different functions in vision. Cones mediate daylight and color vision and in most mammals express M and S opsin photopigments for sensitivity to medium-long and short light wavelengths, respectively. Rods mediate dim light vision ... | 10.1038/nrn2880 | This report refines the transcriptional regulatory networks and places RORβ upstream of NRL in rod differentiation. |
10.1162/089892900562552 | 27,998,243 | We used fMRI to explore the neural substrates involved in the unconscious evaluation of Black and White social groups. Specifically, we focused on the amygdala, a subcortical structure known to play a role in emotional learning and evaluation. In Experiment 1, White American subjects observed faces of unfamiliar Black ... | 10.1038/nrn3800 | An early fMRI investigation of neural correlates of implicit prejudice, focusing on the amygdala. Relative differences in amygdala activity in response to black compared with white faces were associated with a behavioural index of implicit prejudice and startle responses to black versus white faces. |
10.1111/j.1467-9280.2008.02214.x | 16,774,518 | Classic minimal-group studies found that people arbitrarily assigned to a novel group quickly display a range of perceptual, affective, and behavioral in-group biases. We randomly assigned participants to a mixed-race team and used functional magnetic resonance imaging to identify brain regions involved in processing n... | 10.1038/nrn3800 | This study compared the independent effects of race and coalition (team membership) on amygdala responses to faces and showed that when team membership was salient, the amygdala responded to coalition (subject's team or other team) and not race (black or white). This finding demonstrated that the amygdala response to r... |
10.1111/j.0963-7214.2004.01502003.x | 62,434,769 | We examined the hypothesis that unintentional race-biased responses may occur despite the activation of neural systems that detect the need for control. Participants completed a sequential priming task that induced race-biased responses on certain trials while electroencephalography was recorded. The error-related nega... | 10.1038/nrn3800 | This study demonstrated the role of the ACC in the control of racial bias. Using ERPs, the authors found an increase ACC activity to stereotype-based conflict that predicted enhanced control of bias in behaviour. |
10.1162/jocn.2009.21395 | 39,161,628 | Self-regulation is believed to involve changes in motivation and perception that function to promote goal-driven behavior. However, little is known about the way these processes interact during the on-line engagement of self-regulation. The present study examined the coordination of motivation, perception, and action c... | 10.1038/nrn3800 | This study demonstrated the role of the PFC in the behavioural control of racial bias and showed that this effect involves changes in early perceptual attention to racial cues. The study provided initial evidence for a 'motivated perception' account of self-regulation. |
10.1073/pnas.87.7.2506 | 41,468,750 | The antioxidant properties of tryptophan and some of its oxidative metabolites were examined by measuring how efficiently they inhibited peroxyl radical-mediated oxidation of phosphatidylcholine liposomes and B-phycoerythrin. Low micromolar concentrations of 5-hydroxytryptophan, 3-hydroxykynurenine, xanthurenic acid, o... | 10.1038/nrn3257 | Key paper linking metabolites of the kynurenine pathway to redox processes and inflammatory conditions. |
10.1097/00004647-199907000-00007 | 84,376,990 | Two kynurenine hydroxylase inhibitors, ( m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61-8048), have been tested as neuroprotective agents on brain lesions induced by bilateral carotid occlusion in gerbils or by middle cerebral artery occlusion in rats. The per... | 10.1038/nrn3257 | Using well-established animal models of cerebral ischaemia, this is the first paper to demonstrate impressive neuroprotection following systemic administration of a KMO inhibitor. |
10.1073/pnas.95.15.8660 | 102,947,220 | In some organisms longevity, growth, and developmental rate are improved when they are maintained on a light/dark cycle, the period of which “resonates” optimally with the period of the endogenous circadian clock. However, to our knowledge no studies have demonstrated that reproductive fitness per se is improved by res... | 10.1038/nrn1177 | A definitive experimental demonstration of the selective advantage conferred by a circadian clock. |
10.1126/science.288.5466.682 | 104,384,558 | In multicellular organisms, circadian oscillators are organized into multitissue systems which function as biological clocks that regulate the activities of the organism in relation to environmental cycles and provide an internal temporal framework. To investigate the organization of a mammalian circadian system, we co... | 10.1038/nrn1177 | The first demonstration of autonomous circadian timing in rat peripheral tissues, revealed at the molecular level by the Per::luc transgene. |
10.1046/j.1460-9568.2003.02425.x | 19,252,444 | Abstract Expression of coherent and rhythmic circadian (≈ 24 h) variation of behaviour, metabolism and other physiological processes in mammals is governed by a dominant biological clock located in the hypothalamic suprachiasmatic nuclei (SCN). Photic entrainment of the SCN circadian clock is mediated, in part, by vaso... | 10.1038/nrn1177 | References 17 and 18 show that extracellular activation through VPAC2 receptors is necessary to sustain the core molecular oscillation of SCN neurons. |
10.1126/science.1057499 | 41,569,170 | Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are “morning larks” with a 4-hour advance of the sleep, temperature, and melatonin rhythms. Here we report localization of the FASPS gene near the telomere of chromosome 2q. A strong candidate gene (h ... | 10.1038/nrn1177 | Shows a clear biochemical linkage between a human clock gene mutation and a marked sleep disorder. |
10.1126/science.288.5465.483 | 62,270,073 | The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the ... | 10.1038/nrn1177 | A landmark piece of work defining the molecular genetic basis of the first described mutation of circadian periodicity in a mammal. |
10.1126/science.278.5343.1632 | 104,123,661 | Transgenic Drosophila that expressed either luciferase or green fluorescent protein driven from the promoter of the clock gene period were used to monitor the circadian clock in explanted head, thorax, and abdominal tissues. The tissues (including sensory bristles in the leg and wing) showed rhythmic bioluminescence, a... | 10.1038/nrn1177 | References 54 and 55 are the original reports of self-sustaining, Per -based peripheral circadian oscillators in Drosophila |
10.1126/science.291.5503.490 | 41,570,069 | Circadian rhythms of behavior are driven by oscillators in the brain that are coupled to the environmental light cycle. Circadian rhythms of gene expression occur widely in peripheral organs. It is unclear how these multiple rhythms are coupled together to form a coherent system. To study such coupling, we investigated... | 10.1038/nrn1177 | References 78 and 79 showed that restricted feeding can entrain the autonomous circadian clockwork of the liver. |
10.1084/jem.20061931 | 40,882,224 | Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targe... | 10.1038/nrn.2018.13 | This study provides genetic and pharmacological evidence that inhibition of the fibrin–CD11b/CD18 interaction attenuates neuroinflammation without an adverse effect in blood coagulation. |
10.1152/ajpregu.00828.2005 | 63,142,711 | Evidence suggests that IL-1β is involved in promoting physiological nonrapid eye movement (NREM) sleep. IL-1β has also been proposed to mediate NREM sleep enhancement induced by bacteria or their components. Mature and biologically active IL-1β is cleaved from an inactive precursor by a cysteinyl aspartate-specific pro... | 10.1038/nrn2576 | This report that NREM sleep is reduced when cleavage of biologically active IL-1 from its inactive precursor is impeded provides additional evidence of a role for IL-1 in regulating physiological NREM sleep and in the alterations in NREM sleep that follow host defence activation. |
10.1111/j.1460-9568.2004.03469.x | 82,733,105 | Abstract Interleukin‐1β (IL‐1) is a pro‐inflammatory cytokine that has been implicated in the regulation of nonrapid eye movement (nonREM) sleep. IL‐1, IL‐1 receptors and the IL‐1 receptor antagonist (ra) are present normally in discrete brain regions, including the preoptic area (POA) of the hypothalamus and the adjoi... | 10.1038/nrn2576 | These authors demonstrated for the first time that IL-1 applied directly to the hypothalamus inhibits wake-active neurons. The paper also reported increases in discharge rates in a subset of sleep-active neurons. |
10.1152/ajpregu.1984.246.6.r994 | 113,595,280 | When infused into the lateral cerebral ventricles of rabbits, human endogenous pyrogen (EP) preparations induced dose-dependent increases in slow-wave sleep concomitant with increasing body temperature. Heating EP to 70 degrees C destroyed its sleep-promoting and pyrogenic activity. Anisomycin (an antipyretic) prevente... | 10.1038/nrn2576 | This and reference 134 were the first research articles to demonstrate the effects of IL-1 on sleep and the electroencephalogram. |
10.1073/pnas.211268598 | 103,375,086 | Pigment epithelium-derived factor (PEDF), a noninhibitory member of the serpin superfamily, is the most potent inhibitor of angiogenesis in the mammalian ocular compartment. It also has neurotrophic activity, both in the retina and in the central nervous system, and is highly up-regulated in young versus senescent fibr... | 10.1038/nrn1176 | The crystal structure of PEDF provided an accurate structural model by which we can now interpret a number of studies using mutagenesis and peptides to define functional domains. |
10.1523/jneurosci.15-07-04992.1995 | 104,291,819 | Retinal pigment epithelial (RPE) cells form a functional complex with photoreceptor neurons of the retina, interacting through the interphotoreceptor matrix (IPM). We now provide evidence that the gene for pigment epithelium-derived factor (PEDF), a protein possessing neurotrophic and neuronal-survival activities, is h... | 10.1038/nrn1176 | Characterization of the PEDF gene structure and the first evidence for the widespread expression of PEDF in various brain regions and other human tissues. |
10.1073/pnas.90.4.1526 | 83,355,452 | Cultured pigment epithelial cells of the fetal human retina secrete a protein, pigment epithelium-derived factor (PEDF), that induces a neuronal phenotype in cultured human retinoblastoma cells. Morphological changes include the induction of an extensive neurite meshwork and the establishment of corona-like cellular ag... | 10.1038/nrn1176 | The cloning of PEDF gave the first clues about its structure and provided the basis for many expression studies. |
10.1126/science.285.5425.245 | 20,729,299 | In the absence of disease, the vasculature of the mammalian eye is quiescent, in part because of the action of angiogenic inhibitors that prevent vessels from invading the cornea and vitreous. Here, an inhibitor responsible for the avascularity of these ocular compartments is identified as pigment epithelium–derived fa... | 10.1038/nrn1176 | The discovery of a potent antiangiogenic function for PEDF opened a new era in PEDF research. |
10.1152/jn.1998.80.5.2671 | 102,454,726 | Nakamura, Kae, Katsuyuki Sakai, and Okihide Hikosaka. Neuronal activity in medial frontal cortex during learning of sequential procedures. J. Neurophysiol. 80: 2671–2687, 1998. To study the role of medial frontal cortex in learning and memory of sequential procedures, we examined neuronal activity of the presupplementa... | 10.1038/nrn2478 | A landmark neurophysiological study of the effects of disrupting the SMC on the learning of sequential tasks. |
10.1152/jn.1996.76.4.2327 | 50,892,094 | 1. To understand roles played by two cortical motor areas, the presupplementary motor area (pre-SMA) and supplementary motor area (SMA), in changing planned movements voluntarily, cellular activity was examined in two monkeys (Macaca fuscata) trained to perform an arm-reaching task in which they were asked to press one... | 10.1038/nrn2478 | An elegant demonstration of rostro–caudal population differences in cells concerned with switching between movements. |
10.1152/jn.2002.87.5.2577 | 107,301,940 | We used event-related functional magnetic resonance imaging (fMRI) to measure brain activity when subjects were performing identical tasks in the context of either a task-set switch or a continuation of earlier performance. The context, i.e., switching or staying with the current task, influenced medial frontal cortica... | 10.1038/nrn2478 | This seminal study of task switching combined TMS with fMRI to show a dissociation between rostral and caudal regions of the SMC. |
10.1152/jn.00305.2004 | 4,292,206 | It has been suggested on the basis of previous studies involving functional MRI (fMRI) and single-neuron recording that neurons of the supplementary eye field (SEF) and anterior cingulate cortex (ACC) monitor conflict. To test this idea, we carried out microelectrode recording in monkeys performing a color-conditional ... | 10.1038/nrn2478 | A meticulous neurophysiological study that elegantly showed the absence of any single-cell activity in the dorsal cingulate cortex or in the SEF indicating “conflict monitoring” or task-nonspecific “conflict resolution”. |
10.1152/jn.1998.80.6.3247 | 18,682,840 | Shima, Keisetsu and Jun Tanji. Both supplementary and presupplementary motor areas are crucial for the temporal organization of multiple movements. J. Neurophysiol. 80: 3247–3260, 1998. To study the involvement of the supplementary (SMA) and presupplementary (pre-SMA) motor areas in performing sequential multiple movem... | 10.1038/nrn2478 | This paper provided the first evidence that disrupting the SMC interferes with sequences of movements but not with simpler, single movements. |
10.1126/science.1214270 | 103,800,025 | Piercing Botulinum's Defense Botulinum neurotoxins (BoNTs) are poisons that cause muscle paralysis. In the acidic intestine, ingested BoNTs are protected within a progenitor toxin complex. The toxins are released on absorption into the neutral bloodstream. Gu et al. (p. 977 ; see the Perspective by Adler ) present the ... | 10.1038/nrmicro3295 | This study reports the unexpected finding that NTNHA adopts a similar fold to BoNT and that together, the two proteins form an interlocked complex, which suggests that NTNHA stabilizes BoNT and protects the toxin against proteolytic cleavage. |
10.1016/j.febslet.2006.02.074 | 103,786,906 | Botulinum neurotoxins (BoNTs) inhibit neurotransmitter release by selectively cleaving core components of the vesicular fusion machinery. The synaptic vesicle proteins Synaptotagmin‐I and ‐II act as receptors for BoNT/B and BoNT/G. Here we show that BoNT/A also interacts with a synaptic vesicle protein, the synaptic ve... | 10.1038/nrmicro3295 | References 61, 62 and 63 report that the synaptic vesicle protein SV2 functions as a protein receptor for BoNT/A1 and BoNT/E1. |
10.1046/j.1471-4159.1994.63062342.x | 39,814,111 | Abstract: Tetanus toxin (TeNT) is one of the clostridial neurotoxins that act intracellularly to block neurotransmitter release. However, neither the route of entry nor the mechanism by which these toxins gain access to the neuronal cytoplasm has been established definitively. In murine spinal cord cell cultures, relea... | 10.1038/nrmicro3295 | References 75 and 76 show that the acidification of an intracellular compartment by the vesicular ATPase proton pump is a necessary step in nerve intoxication by clostridial neurotoxins. |
10.1073/pnas.82.6.1692 | 102,613,691 | The heavy chains of both botulinum neurotoxin type B and tetanus toxin form channels in planar bilayer membranes. These channels have pH-dependent and voltage-dependent properties that are remarkably similar to those previously described for diphtheria toxin. Selectivity experiments with anions and cations show that th... | 10.1038/nrmicro3295 | This is the first study to describe the formation of ion channels by clostridial neurotoxins in planar lipid bilayers. |
10.1016/j.febslet.2012.11.007 | 80,563,901 | Tetanus and botulinum neurotoxins cause paralysis by cleaving SNARE proteins within the cytosol of nerve terminals. They are endocytosed inside acidic vesicles and the pH gradient across the membrane drives the translocation of their metalloprotease L domain in the cytosol. This domain is linked to the rest of the mole... | 10.1038/nrmicro3295 | This study provides the first evidence that the thioredoxin reductase–thioredoxin protein disulphide-reducing system reduces the inter-chain disulphide bond of clostridial neurotoxins in the neuronal cytosol. |
10.1073/pnas.0805413106 | 104,288,960 | Motor skills can take weeks to months to acquire and can diminish over time in the absence of continued practice. Thus, strategies that enhance skill acquisition or retention are of great scientific and practical interest. Here we investigated the effect of noninvasive cortical stimulation on the extended time course o... | 10.1038/nrn2672 | This paper describes a positive effect of transcranial direct current stimulation on motor learning and, thus, suggests a way that skill acquisition could be augmented. |
10.1080/02643290600576595 | 104,274,324 | Four experiments are reported that examine the ability of cricket batsmen of different skill levels to pick up advance information to anticipate the type and length of balls bowled by swing and spin bowlers. The information available upon which to make the predictive judgements was manipulated through a combination of ... | 10.1038/nrn2672 | A thorough example of how temporal and spatial occlusion techniques can be combined to understand the nature of the expert advantage in anticipation-based decision making. |
10.1002/ar.20580 | 124,133,522 | Abstract Although calcium oxalate (CaOx) renal stones are known to grow attached to renal papillae, and specifically to regions of papillae that contain Randall's plaque (interstitial apatite deposits), the mechanisms of stone overgrowth on plaque are not known. To investigate the problem, we have obtained biopsy speci... | 10.1038/nrneph.2016.101 | A description of the ultrastructure of the interface between plaque and the earliest phase of calcium oxalate stone formation. |
10.1152/ajprenal.90404.2008 | 119,580,236 | A main mechanism of idiopathic hypercalciuria (IH) in calcium stone-forming patients (IHSF) is postprandial reduction of renal tubule calcium reabsorption that cannot be explained by selective reduction of serum parathyroid hormone levels; the nephron site(s) responsible are not as yet defined. Using fourteen 1-h measu... | 10.1038/nrneph.2016.101 | This paper provides evidence that proximal tubule sodium and calcium reabsorption is lower in patients with idiopathic hypercalciuria than in normal individuals, and that this difference contributes to elevated urine calcium excretion. |
10.1126/science.1165557 | 18,827,951 | Infection by human rhinovirus (HRV) is a major cause of upper and lower respiratory tract disease worldwide and displays considerable phenotypic variation. We examined diversity by completing the genome sequences for all known serotypes ( n = 99). Superimposition of capsid crystal structure and optimal-energy RNA confi... | 10.1038/nrmicro2801 | Complete sequencing of 99 serotypes of RVs identifies conserved RNA motifs and clade-specific diversity, and reveals a new species of RV, RV-D |
10.1084/jem.20020943 | 39,901,593 | Infants experiencing severe respiratory syncytial virus (RSV) bronchiolitis have an increased frequency of wheeze and asthma in later childhood. Since most severe RSV infections occur between the 8th and 24th postnatal week, we examined whether age at first infection determines the balance of cytokine production and lu... | 10.1038/nrmicro2801 | This investigation elegantly demonstrates that neonatal infection with RSV in mice causes increased disease severity on reinfection later in life. The increased severity is associated with enhanced T H 2 type responses |
10.4049/jimmunol.1001758 | 57,229,364 | Abstract Severe respiratory syncytial virus (RSV) infection has long been associated with an increased risk for the development of childhood asthma and exacerbations of this disorder. Despite much research into the induction of Th2 responses by allergens and helminths, the factors associated with viral infection that p... | 10.1038/nrmicro2801 | This study demonstrates the important role of natural killer cell-derived IFNλ in controlling IL-25 production during human RSV infection. This study highlights the potential for viruses to elicit T H 2 type immune responses in the absence of IFNλ |
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