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10.1073/pnas.0905390106
109,109,936
Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now sho...
10.1038/nrn2936
The first demonstration that NgR is linked to specific aspects of memory in vivo
10.1126/science.1128657
107,254,070
Analogous to learning and memory storage, long-term potentiation (LTP) is divided into induction and maintenance phases. Testing the hypothesis that the mechanism of LTP maintenance stores information requires reversing this mechanism in vivo and finding out whether long-term stored information is lost. This was not pr...
10.1038/nrn2590
This paper identified PKMζ as the only molecule currently known to maintain LTM.
10.1126/science.1095760
104,411,637
The idea that new memories undergo a time-dependent consolidation process after acquisition has received considerable experimental support. More controversial has been the demonstration that established memories, once recalled, become labile and sensitive to disruption, requiring “reconsolidation” to become permanent. ...
10.1038/nrn2590
This paper showed that the mechanisms that mediate consolidation and reconsolidation can be doubly dissociated, suggesting that the differences between consolidation and reconsolidation cannot be explained by use of asymmetric protocols.
10.1126/science.1150541
20,797,361
Reactivated memory undergoes a rebuilding process that depends on de novo protein synthesis. This suggests that retrieval is dynamic and serves to incorporate new information into preexisting memories. However, little is known about whether or not protein degradation is involved in the reorganization of retrieved memor...
10.1038/nrn2590
This paper showed that proteins must be degraded in order to transform a reactivated memory from a fixed to a labile state, suggesting that after reactivation degraded proteins need to be replaced through protein synthesis or else the reactivated memory cannot be re-stabilized.
10.1126/science.160.3827.554
61,009,793
Rats had a memory loss of a fear response when they received an electroconvulsive shock 24 hours after the fear-conditioning trial and preceded by a brief presentation of the conditioned stimulus. No such loss occurred when the conditioned stimulus was not presented. The memory loss in animals given electroconvulsive s...
10.1038/nrn2590
This seminal paper provided the first description of the reconsolidation phenomenon but, for historical reasons, reconsolidation remained outside the mainstream literature until 2000.
10.1523/jneurosci.2049-06.2006
123,584,626
It has been reported that consolidated memories can return to a labile state when reactivated and undergo a process of re-storage, termed reconsolidation, required for later recall. We investigated memory for a nonassociative learning task (habituation) and found that memory for this task also undergoes reconsolidation...
10.1038/nrn2590
This paper showed that blocking reconsolidation in nematodes reverses the molecular correlates of LTM to those of naive animals.
10.1126/science.1086881
85,551,457
In memory consolidation, the memory trace stabilizes and becomes resistant to certain amnesic agents. The textbook account is that for any memorized item, consolidation starts and ends just once. However, evidence has accumulated that upon activation in retrieval, the trace may reconsolidate. Whereas some authors repor...
10.1038/nrn2590
This elegant study showed in two different species that consolidation of extinction learning for a memory could inhibit reconsolidation for this memory.
10.1101/lm.1022308
39,412,309
Understanding the dynamics of memory change is one of the current challenges facing cognitive neuroscience. Recent animal work on memory reconsolidation shows that memories can be altered long after acquisition. When reactivated, memories can be modified and require a restabilization (reconsolidation) process. We recen...
10.1038/nrn2590
This paper demonstrated in humans that episodic memory reconsolidation depends on re-exposure to the spatial context in which the original learning occurred, suggesting that the spatial context is crucial for inducing reconsolidation in human episodic memory.
10.1084/jem.20110039
80,449,560
Apicomplexa are important pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. Apicomplexan parasites contain a relict chloroplast, the apicoplast. The apicoplast is indispensable and an attractive drug target. The apicoplast is home to a 1-deoxy-d-xylulose-5-phosphate (DOXP) pa...
10.1038/nrmicro3139
These authors demonstrated that the insensitivity of T. gondii to fosmidomycin is caused by non-internalization of the drug and that expression of a bacterial GlpT allows fosmidomycin penetration and activity.
10.1083/jcb.124.4.449
41,740,586
This work describes two unusual features of membrane development in a eukaryotic cell. (a) The induction of an extensive network of tubovesicular membranes by the malaria parasite Plasmodium falciparum in the cytoplasm of the mature erythrocyte, and its visualization with two ceramide analogues C5-DMB-ceramide and C6-N...
10.1038/nrmicro3139
These authors show that P. falciparum blood forms elaborate a TVN derived from the parasitophorous vacuole membrane by exporting their own sphingomyelin synthase into the host cell, resulting in the local production of sphingolipids in the network.
10.1091/mbc.e12-11-0827
99,627,713
The obligate intracellular protozoan Toxoplasma gondii actively invades mammalian cells and, upon entry, forms its own membrane-bound compartment, named the parasitophorous vacuole (PV). Within the PV, the parasite replicates and scavenges nutrients, including lipids, from host organelles. Although T. gondii can synthe...
10.1038/nrmicro3139
This study shows that although T. gondii can synthesize sphingolipids de novo , it also scavenges these lipids from the host Golgi apparatus by subverting the structure and functions of this organelle.
10.1083/jcb.112.2.267
60,548,758
Several intraerythrocytic growth cycles of Plasmodium falciparum could be achieved in vitro using a serum free medium supplemented only with a human high density lipoprotein (HDL) fraction (d = 1.063-1.210). The parasitemia obtained was similar to that in standard culture medium containing human serum. The parasite dev...
10.1038/nrmicro3139
This study details how plasma HDL particles support the growth of P. falciparum blood forms by supplying essential lipids, including cholesterol, to the parasite.
10.1111/j.1600-0854.2012.01398.x
82,012,020
The obligate intracellular liver stage of the Plasmodium parasite represents a bottleneck in the parasite life cycle and remains a promising target for therapeutic intervention. During this stage, parasites undergo dramatic morphological changes and achieve one of the fastest replication rates among eukaryotic species....
10.1038/nrmicro3139
This paper shows that Plasmodium berghei liver forms reroute host endocytic structures to the parasitophorous vacuole and use the contents of these organelles as a source of nutrients derived from the medium.
10.1083/jcb.149.1.167
38,903,492
The obligate intracellular protozoan Toxoplasma gondii resides within a specialized parasitophorous vacuole (PV), isolated from host vesicular traffic. In this study, the origin of parasite cholesterol was investigated. T. gondii cannot synthesize sterols via the mevalonate pathway. Host cholesterol biosynthesis remain...
10.1038/nrmicro3139
This study shows that T. gondii is auxotrophic for LDL-derived cholesterol and that interference with LDL endocytosis in the host cell reduces parasite replication.
10.1111/mmi.12142
124,881,408
Summary Lipid bodies are eukaryotic structures for temporary storage of neutral lipids such as acylglycerols and steryl esters. Fatty acyl‐ CoA and cholesterol are two substrates for cholesteryl ester ( CE ) synthesis via the ACAT reaction. The intracellular parasite T oxoplasma gondii is incapable of sterol synthesis ...
10.1038/nrmicro3139
This study shows that T. gondii expresses two ACAT enzymes involved in the storage of cholesterol and that the parasite is particularly vulnerable to ACAT inhibitors.
10.1146/annurev-med-052209-100430
82,879,883
The brain is the key organ of stress processes. It determines what individuals will experience as stressful, it orchestrates how individuals will cope with stressful experiences, and it changes both functionally and structurally as a result of stressful experiences. Within the brain, a distributed, dynamic, and plastic...
10.1038/nrn3138
A recent overview of plasticity of the brain based on animal model studies and human brain research. The overview is based on the conceptual model of allostasis and allostatic load (see reference 3), in which the brain is the central organ of stress and adaptation and regulates and responds to stress hormones and other...
10.1073/pnas.0507572102
42,610,585
The adrenal hormone corticosterone transcriptionally regulates responsive genes in the rodent hippocampus through nuclear mineralocorticoid and glucocorticoid receptors. Via this genomic pathway the hormone alters properties of hippocampal cells slowly and for a prolonged period. Here we report that corticosterone also...
10.1038/nrn3138
This study used patch-clamp recordings to show that applying corticosterone onto hippocampal slices rapidly and reversibly enhances glutamate release and transmission through a non-genomic pathway involving membrane-located mineralocorticoid receptors.
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/nrn3138
This study demonstrates AMPAR-mediated effects of NMDAR antagonists on synaptic plasticity and behaviour. The paper provides strong evidence to suggest that the antidepressant and anti-stress effects of NMDAR antagonists such as ketamine are, at least in part, mediated by increased excitation of postsynaptic AMPARs.
10.1073/pnas.89.9.3830
875,141
The recently characterized corticosteroid receptor on amphibian neuronal membranes appears to mediate rapid, stress-induced changes in male reproductive behaviors. Because the transduction mechanisms associated with this receptor are unknown, we performed radioligand binding studies to determine whether this steroid re...
10.1038/nrn3138
A key paper showing G-protein-like glucocorticoid receptors in the brain of a newt, Taricha granulosa , which led to the finding of rapid glucocorticoid signalling for the endocannabinoid systems summarized in reference 201. However, recent work (reference 209) showing Ru486 antagonism in the glucocorticoid regulation ...
10.1126/science.1071184
124,251,950
Harvesting light to produce energy and oxygen (photosynthesis) is the signature of all land plants. This ability was co-opted from a precocious and ancient form of life known as cyanobacteria. Today these bacteria, as well as microscopic algae, supply oxygen to the atmosphere and churn out fixed nitrogen in Earth's vas...
10.1038/nrmicro2778
This concept paper outlines the interconnectedness between atmospheric transformation and microbial metabolism now and throughout evolutionary time.
10.1146/annurev.marine.010908.163855
123,187,115
Ocean warming and increased stratification of the upper ocean caused by global climate change will likely lead to declines in dissolved O 2 in the ocean interior (ocean deoxygenation) with implications for ocean productivity, nutrient cycling, carbon cycling, and marine habitat. Ocean models predict declines of 1 to 7%...
10.1038/nrmicro2778
This paper reviews the evidence for global oxygen loss in the oceans over the past 50 years and discusses potential consequences of continued deoxygenation on the ecology and biogeochemistry of marine ecosystems.
10.1126/science.1156401
20,845,774
Dead zones in the coastal oceans have spread exponentially since the 1960s and have serious consequences for ecosystem functioning. The formation of dead zones has been exacerbated by the increase in primary production and consequent worldwide coastal eutrophication fueled by riverine runoff of fertilizers and the burn...
10.1038/nrmicro2778
This influential concept article describes the ecological consequences of episodic or prolonged oxygen starvation on coastal marine ecosystems.
10.1126/science.1196889
104,217,097
Cryptic Sulfur Cycling Aerobic bacteria and ocean circulation patterns control the formation and distribution of oxygen-minimum zones at moderate depth in the oceans. These habitats host microorganisms that thrive on other metabolic substrates in the absence of oxygen—most commonly, metabolizing thermodynamically favor...
10.1038/nrmicro2778
This paper provides the first report of SO 4 2− reduction and concomitant sulphide oxidation in the ETSP OMZ.
10.1126/science.1203690
124,085,094
Recent studies suggest that unidentified prokaryotes fix inorganic carbon at globally significant rates in the immense dark ocean. Using single-cell sorting and whole-genome amplification of prokaryotes from two subtropical gyres, we obtained genomic DNA from 738 cells representing most cosmopolitan lineages. Multiple ...
10.1038/nrmicro2778
This paper reveals the hidden metabolic powers of Arctic96BD-19 and SAR324 bacteria using single-cell genomics techniques.
10.1111/j.1462-2920.2010.02400.x
62,314,448
Summary Simultaneous characterization of taxonomic composition, metabolic gene content and gene expression in marine oxygen minimum zones (OMZs) has potential to broaden perspectives on the microbial and biogeochemical dynamics in these environments. Here, we present a metatranscriptomic survey of microbial community m...
10.1038/nrmicro2778
This article provides the first gene expression profiles for sulphide oxidation, denitrification, anammox and nitrification in the ETSP OMZ.
10.1101/gr.104521.109
17,564,543
Microbes are the most abundant and diverse organisms on Earth. In contrast to macroscopic organisms, their environmental preferences and ecological interdependencies remain difficult to assess, requiring laborious molecular surveys at diverse sampling sites. Here, we present a global meta-analysis of previously sampled...
10.1038/nrmicro2778
This paper describes a useful method for detecting co-occurrence patterns within and between microbial communities using geo-referenced taxonomic and functional-gene information.
10.1126/science.1060161
86,443,661
An afterimage induced by prior adaptation to a visual stimulus is believed to be due to bleaching of photochemical pigments or neural adaptation in the retina. We report a type of afterimage that appears to require cortical adaptation. Fixating a neon-color spreading configuration led not only to negative afterimages c...
10.1038/nrn1869
A clear demonstration that filling-in generates afterimage, which indicates that filling-in is accompanied by some active neural processes.
10.1068/p190497
122,359,969
The perception of transparency is highly dependent on luminance and perceived depth. An image region is seen as transparent if it is of intermediate luminance relative to adjacent image regions, and if it is perceived in front of another region and has a boundary which provides information that an object is visible thr...
10.1038/nrn1869
Shows that filling-in is dramatically affected by the three-dimensional interpretation of the scene.
10.1128/aem.54.6.1472-1480.1988
40,690,332
A dissimilatory Fe(III)- and Mn(IV)-reducing microorganism was isolated from freshwater sediments of the Potomac River, Maryland. The isolate, designated GS-15, grew in defined anaerobic medium with acetate as the sole electron donor and Fe(III), Mn(IV), or nitrate as the sole electron acceptor. GS-15 oxidized acetate ...
10.1038/nrmicro3347
This landmark paper provides the first evidence of organic C oxidation coupled to metal respiration (that is, to the transfer of electrons to Fe( III
10.1128/aem.62.4.1458-1460.1996
104,088,623
Enrichment and pure cultures of nitrate-reducing bacteria were shown to grow anaerobically with ferrous iron as the only electron donor or as the additional electron donor in the presence of acetate. The newly observed bacterial process may significantly contribute to ferric iron formation in the suboxic zone of aquati...
10.1038/nrmicro3347
This work is the first demonstration of microbial Fe( II ) oxidation coupled to nitrate reduction.
10.1111/gbi.12019
62,383,002
Abstract Nitrate‐reducing, Fe(II)‐oxidizing bacteria were suggested to couple with enzymatic Fe(II) oxidation to nitrate reduction. Denitrification proceeds via intermediates ( , NO) that can oxidize Fe(II) abiotically at neutral and particularly at acidic pH . Here, we present a revised Fe(II) quantification protocol ...
10.1038/nrmicro3347
This paper is an excellent example of coupled biotic–abiotic reactions in biogeochemical processes and describes how microbially driven denitrification leads to the formation of a reactive chemical species (that is, NO 2 − ) that prevents the unambiguous identification of enzymatic Fe( II ) oxidation.
10.1038/ismej.2010.173
19,511,123
Abstract Neutrophilic Fe-oxidizing bacteria (FeOB) are often identified by their distinctive morphologies, such as the extracellular twisted ribbon-like stalks formed by Gallionella ferruginea or Mariprofundus ferrooxydans. Similar filaments preserved in silica are often identified as FeOB fossils in rocks. Although it...
10.1038/nrmicro3347
This work tracks the formation of organic stalks by Fe( II )-oxidizing bacteria and suggests why this localization of Fe mineral formation away from the cell occurs and how it could be used as a biosignature.
10.1126/science.1237331
80,282,588
Superoxide and other reactive oxygen species (ROS) originate from several natural sources and profoundly influence numerous elemental cycles, including carbon and trace metals. In the deep ocean, the permanent absence of light precludes currently known ROS sources, yet ROS production mysteriously occurs. Here, we show ...
10.1038/nrmicro3347
This paper shows that superoxide is produced by diverse heterotrophic organisms, which expands superoxide production from sunlit environments into darker waters.
10.1111/j.1365-2958.2007.05783.x
107,164,439
Summary Dissimilatory reduction of metal (e.g. Fe, Mn) (hydr)oxides represents a challenge for microorganisms, as their cell envelopes are impermeable to metal (hydr)oxides that are poorly soluble in water. To overcome this physical barrier, the Gram‐negative bacteria Shewanella oneidensis MR‐1 and Geobacter sulfurredu...
10.1038/nrmicro3347
This work highlights the role of multihaem c -type cytochromes in bacterial electron transfer to solid metal oxides and hydroxides.
10.1073/pnas.0710525105
104,382,687
Bacteria able to transfer electrons to metals are key agents in biogeochemical metal cycling, subsurface bioremediation, and corrosion processes. More recently, these bacteria have gained attention as the transfer of electrons from the cell surface to conductive materials can be used in multiple applications. In this w...
10.1038/nrmicro3347
References 123 and 124 demonstrate that the Fe( III )-reducing bacteria S. oneidensis MR-1 produces and secretes flavins that mediate extracellular electron transfer and therefore potentially facilitate the interaction between bacteria and their solid ferric substrate.
10.1126/science.1089134
20,869,312
A neuroimaging study examined the neural correlates of social exclusion and tested the hypothesis that the brain bases of social pain are similar to those of physical pain. Participants were scanned while playing a virtual ball-tossing game in which they were ultimately excluded. Paralleling results from physical pain ...
10.1038/nrn3231
This was the first study to examine the neural correlates of social pain in humans and the first to show activation of affective pain-related neural regions in response to social exclusion.
10.1126/science.277.5328.968
60,159,362
Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious s...
10.1038/nrn3231
This study creatively highlights the role of the dACC in the affective component of pain.
10.1177/0956797610374741
39,363,728
Pain, whether caused by physical injury or social rejection, is an inevitable part of life. These two types of pain—physical and social—may rely on some of the same behavioral and neural mechanisms that register pain-related affect. To the extent that these pain processes overlap, acetaminophen, a physical pain suppres...
10.1038/nrn3231
This study demonstrated that Tylenol, a physical pain reliever, could reduce social pain as well.
10.1073/pnas.1102693108
83,329,012
How similar are the experiences of social rejection and physical pain? Extant research suggests that a network of brain regions that support the affective but not the sensory components of physical pain underlie both experiences. Here we demonstrate that when rejection is powerfully elicited—by having people who recent...
10.1038/nrn3231
This study included both a physical and social pain task, and highlighted overlapping neural activity in response to both tasks.
10.1073/pnas.0812612106
19,378,994
Scientific understanding of social pain—the hurt feelings resulting from social rejection, separation, or loss—has been facilitated by the hypothesis that such feelings arise, in part, from some of the same neural and neurochemical systems that generate the unpleasant feelings resulting from physical pain. Accordingly,...
10.1038/nrn3231
This study demonstrated that a gene linked with physical pain sensitivity ( OPRM1 ) is also associated with rejection sensitivity.
10.1002/hipo.20520
20,389,267
Abstract Individual medial entorhinal cortex (mEC) ‘grid’ cells provide a representation of space that appears to be essentially invariant across environments, modulo simple transformations, in contrast to multiple, rapidly acquired hippocampal maps; it may therefore be established gradually during rodent development. ...
10.1038/nrn3766
This paper proposes the only model for grid cells that is not primarily based on path integration. Grids are formed through a self-organizing mechanism that combines Hebbian plasticity, feedforward spatially selective input and neuronal adaptation.
10.1126/science.1134108
62,618,222
Ubiquitin-positive, tau- and α-synuclein–negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease pro...
10.1038/nrn2420
This study shows that the tau-negative, ubiquitin-positive lesions in some forms of frontotemporal dementia and amyotrophic lateral sclerosis contain the protein TDP-43.
10.1126/science.1113694
103,827,988
Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, ne...
10.1038/nrn2420
This study shows that NFT formation is not related to functional impairment in mice.
10.1126/science.1141736
100,515,169
Many potential treatments for Alzheimer's disease target amyloid-β peptides (Aβ), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Aβ-induced cognitive impairments. Here, we found that re...
10.1038/nrn2420
This study shows that tau reduction protects from Aβ-mediated toxicity and excitotoxicity.
10.1126/science.1105681
103,817,875
We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associate...
10.1038/nrn2420
This study identifies correlates of impaired axonal transport in APP transgenic mice and AD brains. Formation of spheroids increases with reduced kinesin function.
10.1126/science.1062382
83,188,826
The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, the mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model of tau-related neurodegenerative disease by expressing wild-type and mutant forms of human ta...
10.1038/nrn2420
This study shows in D. melanogaster that tau-mediated neurodegeneration can occur in the absence of NFT formation.
10.1073/pnas.97.20.11038
45,559,644
To determine the genetic causes and molecular mechanisms responsible for neurobehavioral differences in mice, we used highly parallel gene expression profiling to detect genes that are differentially expressed between the 129SvEv and C57BL/6 mouse strains at baseline and in response to seizure. In addition, we identifi...
10.1038/nrn2420
This study shows differentially regulated genes in subregions of the hippocampus.
10.1002/ana.20009
41,758,566
Abstract This report describes the first human study of a novel amyloid‐imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound‐B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex...
10.1038/nrn2420
This study shows that the Pittsburgh Compound-B (PIB) is a suitable PET tracer in vivo
10.1073/pnas.2034101100
79,386,785
The lack of a specific biomarker makes preclinical diagnosis of Alzheimer's disease (AD) impossible, and it precludes assessment of therapies aimed at preventing or reversing the course of the disease. The development of a tool that enables direct, quantitative detection of the amyloid-β deposits found in the disease w...
10.1038/nrn2420
This study introduces the Pittsburgh Compound-B (PIB) that binds to Aβ plaques in vivo
10.1073/pnas.092136199
83,183,079
Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar β-amyloid peptide (Aβ); neurofibrillary tangles represent intracellular bu...
10.1038/nrn2420
This study shows in primary neuronal cultures of Tau −/− mice that tau is needed for Aβ-mediated toxicity.
10.1126/science.1131864
62,551,961
Protein aggregation is an established pathogenic mechanism in Alzheimer's disease, but little is known about the initiation of this process in vivo. Intracerebral injection of dilute, amyloid-β (Aβ)–containing brain extracts from humans with Alzheimer's disease or β-amyloid precursor protein (APP) transgenic mice induc...
10.1038/nrn2420
This study shows shared properties between prions and Aβ with regards to host and agent dictating pathology.
10.1126/science.1132341
62,565,445
Although BACE1 (beta-site amyloid precursor protein–cleaving enzyme 1) is essential for the generation of amyloid-b peptide in Alzheimer's disease, its physiological function is unclear. We found that very high levels of BACE1 were expressed at time points when peripheral nerves become myelinated. Deficiency of BACE1 r...
10.1038/nrn2420
This study identifies a role for the β-secretase BACE in processing neuregulin.
10.1073/pnas.98.4.2017
60,814,142
Choline acetyltransferase (ChAT; EC 2.3.1.6 ) catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. Mutations in genes encoding ChAT affecting motility exist in Caenorhabditis elegans and Drosophila , but no CHAT mutations have been observed in humans to date. He...
10.1038/nrn1101
This is the first description of mutations in CHAT in humans. This study also identifies the kinetic abnormalities in expressed CHAT mutants that impair its catalytic efficiency and impair ACh resynthesis.
10.1073/pnas.95.16.9654
82,014,109
In skeletal muscle, acetylcholinesterase (AChE) exists in homomeric globular forms of type T catalytic subunits (ACHE T ) and heteromeric asymmetric forms composed of 1, 2, or 3 tetrameric ACHE T attached to a collagenic tail (ColQ). Asymmetric AChE is concentrated at the endplate (EP), where its collagenic tail anchor...
10.1038/nrn1101
This is the first report of the cloning of COLQ cDNA, chromosomal localization and determination of the genomic structure of COLQ , and identification of truncating mutations in COLQ that result in ACHE deficiency.
10.1113/jphysiol.1973.sp010248
100,709,790
1. Acetylcholine (ACh) noise and miniature end‐plate potentials were recorded with focal external micro‐electrodes. 2. The effect of prostigmine on the time course of the ‘molecular’ and ‘quantal’ transmitter actions was studied. Prostigmine (10 −6 g/ml.) has little or no effect on the duration of the molecular ‘gating...
10.1038/nrn1101
An early classical study explaining why inhibition of ACHE prolongs the synaptic response.
10.1073/pnas.92.3.758
122,221,197
In a congenital myasthenic syndrome with a severe endplate myopathy, patch-clamp studies revealed markedly prolonged acetylcholine receptor (AChR) channel openings. Molecular genetic analysis of AChR subunit genes demonstrated a heterozygous adenosine-to-cytosine transversion at nucleotide 790 in exon 8 of the epsilon-...
10.1038/nrn1101
The first mutation identified to cause a CMS. A slow-channel syndrome was shown to result from a Thr to Pro mutation in TMD2 of the ε-subunit. Individual channel opening episodes were markedly prolonged, and openings in the absence of agonist increased in frequency. The findings explained the presence of endplate myopa...
10.1073/pnas.86.7.2199
728,325
The energetics and kinetics of activation of the acetylcholine receptor are evaluated in the context of optimizing rapid synaptic transmission. Physiological needs are used as the basis for estimating optimal values for the closed-to-open channel equilibrium constants of the liganded and unliganded receptor. An estimat...
10.1038/nrn1101
This paper rationalized the need for two ACh binding sites per receptor using the concept that the open state binds ACh more tightly than the closed state. It also further explained that at least one of the binding sites has to release ACh quickly to rapidly terminate the response.
10.1085/jgp.96.2.395
109,185,171
The experiments described examine single channel currents recorded through Torpedo acetylcholine receptor channels stably expressed by a mouse fibroblast cell line. Closed-duration histograms were constructed from currents elicited by 0.5-300 microM acetylcholine (ACh). The concentration dependence of closed durations ...
10.1038/nrn1101
Provides the complete analysis of AChR kinetics by fitting a kinetic scheme to single-channel open and closed dwell times. The deduced rate constants showed distinct agonist binding affinities for the two binding sites, and disclosed rapid rates of ACh binding and channel opening.
10.1085/jgp.116.3.449
58,896,277
We describe the genetic and kinetic defects in a congenital myasthenic syndrome due to the mutation εA411P in the amphipathic helix of the acetylcholine receptor (AChR) ε subunit. Myasthenic patients from three unrelated families are either homozygous for εA411P or are heterozygous and harbor a null mutation in the sec...
10.1038/nrn1101
Using a new method for kinetic analysis of single-channel currents this study obtained kinetic parameters for individual epochs of receptor activity. It identified a region of the AChR exposed to the cytoplasm that produces uniformity of AChR activation episodes, and highlighted the concept of a corrugated energy lands...
10.1002/ana.410400521
101,810,219
Abstract We describe a congenital myasthenic syndrome associated with severe end‐plate (EP) acetylcholine receptor (AChR) deficiency not associated with an EP myopathy, and with evidence of immature AChR, containing the γ instead of the epsiv; subunit (γ‐AChR) at the EPs. Molecular genetic analysis of AChR‐subunit gene...
10.1038/nrn1101
Provides evidence that the persistent expression of the foetal AChR γ-subunit can partially compensate for null mutations in both alleles of the AChR ε-subunit and can therefore rescue the phenotype.
10.1046/j.1471-4159.2001.00203.x
4,217,147
The cellular events mediating necrotic neuron death are now reasonably well understood, and involve excessive extracellular accumulation of glutamate and free cytosolic calcium. When such necrotic neurological insults occur, neurons are not passively buffeted, but instead mobilize a variety of defenses in an attempt to...
10.1038/nrn1927
In this paper, the author reviewed the often overlooked protective mechanisms that are activated by ischaemia; although endogenous to the tissue, these mechanisms are largely different from those induced by preconditioning per se
10.1073/pnas.0232966100
109,162,735
Sublethal insults can induce tolerance to subsequent stressors in neurons. As cell death activators such as ROS generation and decreased ATP can initiate tolerance, we tested whether other cellular elements normally associated with neuronal injury could add to this process. In an in vivo model of ischemic tolerance, we...
10.1038/nrn1927
This study demonstrated in vivo that focal ischaemic preconditioning activates caspase 3 over a time frame coincident with tolerance, and that, in vitro , this activation was required for preconditioning-induced neuroprotection.
10.1073/pnas.94.20.10873
38,412,011
Immune mechanisms contribute to cerebral ischemic injury. Therapeutic immunosuppressive options are limited due to systemic side effects. We attempted to achieve immunosuppression in the brain through oral tolerance to myelin basic protein (MBP). Lewis rats were fed low-dose bovine MBP or ovalbumin (1 mg, five times) b...
10.1038/nrn1927
The first report to demonstrate that active immunologic tolerance secondary to preconditioning by intentional presentation of CNS antigens can be neuroprotective in cerebral ischaemia.
10.1073/pnas.92.10.4666
101,147,098
Preconditioning with sublethal ischemia protects against neuronal damage after subsequent lethal ischemic insults in hippocampal neurons. A pharmacological approach using agonists and antagonists at the adenosine A1 receptor as well as openers and blockers of ATP-sensitive K+ channels has been combined with an analysis...
10.1038/nrn1927
This study provided causal data for the involvement of adenosine and K ATP channels in the induction of ischaemic tolerance; since this early paper, experimental support for these mechanisms has continued to accumulate.
10.1097/00004647-200103000-00007
122,853,949
In the rat, 60 minutes of transient ischemia to the middle cerebral artery results in infarction of the caudate putamen. Ischemic preconditioning with 20 minutes of transient focal ischemia produced tolerance (attenuated infarction volume) to 60 minutes of subsequent focal ischemia administered three days, five days, o...
10.1038/nrn1927
Using BCL2 antisense oligonucleotides, the authors demonstrated that tolerance is dependent on preconditioning-induced expression of BCL2; in doing so, a foundation for the anti-apoptotic basis of ischaemic tolerance was established.
10.1152/physiolgenomics.00046.2004
82,172,618
Remote ischemic preconditioning (IPC) reduces tissue injury caused by ischemia-reperfusion (IR) in distant organs. We tested the hypothesis that remote IPC (rIPC) modifies inflammatory gene transcription in humans. Using a microarray method, we demonstrated that a simple model of brief forearm ischemia suppresses proin...
10.1038/nrn1927
Microarray analyses of human blood cells after preconditioning by brief limb ischaemia revealed gene expression changes in circulating leukocytes, with important implications regarding the mechanistic basis of ischaemic tolerance and the need to further expand the 'neurovascular unit' concept.
10.1002/glia.20204
29,311,867
Abstract Following focal cerebral ischemia (“stroke”) a complex and dynamic interaction of vascular cells, glial cells, and neurons determines the extent of the ensuing lesion. Traditionally, the focus has been on mechanisms of damage , while recently it has become clear that endogenous mechanisms of protection are equ...
10.1038/nrn1927
Recent review that served as the first definitive summary of the emerging field of glial cell preconditioning and the mechanisms by which glial responses contribute to ischaemic tolerance.
10.1073/pnas.93.18.9493
83,244,087
We develop a unifying theory of hypoxia tolerance based on information from two cell level models (brain cortical cells and isolated hepatocytes) from the highly anoxia tolerant aquatic turtle and from other more hypoxia sensitive systems. We propose that the response of hypoxia tolerant systems to oxygen lack occurs i...
10.1038/nrn1927
A seminal paper that conceptually integrated many previous findings in the comparative physiology of hypoxia- and anoxia-adapted species.
10.1101/gad.14.4.414
128,027,295
Translation initiation on eukaryotic mRNAs involves 40S ribosome association with mRNA caps (m 7 GpppN), mediated by initiation factor eIF4F. 40S eukaryotic ribosomes and initiation factors undergo 5′ scanning to the initiation codon, with no known role for complementarity between eukaryotic 18S rRNA and the 5′ noncodi...
10.1038/nrmicro2655
Together with references 27 and 29, an article that provides a comprehensive analysis of ribosomes shunting in uninfected and adenovirus-infected cells.
10.1101/gad.14.7.817
129,478,596
The shunt model predicts that small ORFs (sORFs) within the cauliflower mosaic virus (CaMV) 35S RNA leader and downstream ORF VII are translated by different mechanisms, that is, scanning–reinitiation and shunting, respectively. Wheat germ extract (WGE) and rabbit reticulocyte lysate (RRL) in vitro translation systems ...
10.1038/nrmicro2655
A demonstration that shunting in the CaMV 35S RNA leader involves translation of a small uORF followed by re-initiation downstream of the ribosomal-shunt landing site.
10.1101/gad.1185304
123,771,635
Although the activity of the translation initiation factor eIF4F is regulated in part by translational repressors (4E-BPs) that prevent incorporation of eIF4E, the cap-binding protein, into the initiation complex, the contribution of eIF4E phosphorylation to translational control remains controversial. Here, we demonst...
10.1038/nrmicro2655
A report providing the first evidence that DNA viruses can stimulate eIF4F activity to enhance viral replication.
10.1101/gad.12.1.67
109,028,724
Initiation of translation of hepatitis C virus and classical swine fever virus mRNAs results from internal ribosomal entry. We reconstituted internal ribosomal entry in vitro from purified translation components and monitored assembly of 48S ribosomal preinitiation complexes by toe-printing. Ribosomal subunits (40S) fo...
10.1038/nrmicro2655
The finding that the requirements for 48S pre-initiation complex formation on HCV and CSFV IRESs differ from those of the EMCV IRES, as shown by reconstituting internal ribosome entry in vitro using purified translation components.
10.1101/gad.1957510
4,644,729
Eukaryotic translation initiation begins with ribosomal recruitment of aminoacylated initiator tRNA (Met-tRNA Met i ) by eukaryotic initiation factor eIF2. In cooperation with eIF3, eIF1, and eIF1A, Met-tRNA Met i /eIF2/GTP binds to 40S subunits yielding 43S preinitiation complexes that attach to the 5′-terminal region...
10.1038/nrmicro2655
A study identifying cellular factors that substitute for eIF2 to mediate initiation on viral IRES elements.
10.1101/gad.1832209
58,603,682
Most eukaryotic mRNAs are translated using a cap-dependent mechanism of translation. However, ∼10% of mammalian mRNAs initiate translation using a cap-independent mechanism that is not well understood. These mRNAs contain an internal ribosome entry site (IRES) located in the 5′ untranslated region. The cricket paralysi...
10.1038/nrmicro2655
Work establishing that a cellular ribosomal protein is specifically required for IRES-mediated translation.
10.1101/gad.357006
102,428,191
The double-stranded RNA-dependent protein kinase (PKR) is one of the four mammalian kinases that phosphorylates the translation initiation factor 2α in response to virus infection. This kinase is induced by interferon and activated by double-stranded RNA (dsRNA). Phosphorylation of eukaryotic initiation factor 2α (eIF2...
10.1038/nrmicro2655
The identification of a viral genetic element that supports translation initiation in the presence of phosphorylated eIF2α.
10.1073/pnas.80.14.4546
20,721,391
A syndrome similar to idiopathic parkinsonism developed after intravenous self-administration of an illicit drug preparation in which N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) might have been responsible for the toxicity. In the present study we show that intravenous administration of NMPTP to the rhesus mon...
10.1038/nrn2196
Provided the first demonstration of the highly sucessful MPTP animal model of Parkinson's disease.
10.1002/mds.870060404
102,994,188
Abstract Central to the neural mechanism of MPTP‐induced parkinsonism is overactivity of the subthalamic nucleus. Lesion of the subthalamic nucleus has therefore been performed in two primates with this condition and found to produce a remarkable amelioration of the disorder.
10.1038/nrn2196
Together with reference 66, this classic study showed that lesions of the STN alleviate the symptoms of parkinsonian MPTP-treated monkeys.
10.1523/jneurosci.15-01-00047.1995
83,551,799
The cellular generation and spatial distribution of gamma frequency (40– 100 Hz) activity was examined in the hippocampus of the awake rat. Field potentials and unit activity were recorded by multiple site silicon probes (5- and 16-site shanks) and wire electrode arrays. Gamma waves were highly coherent along the long ...
10.1038/nrn2044
A key paper that analyses the properties of hippocampal gamma oscillations in vivo in the non-anesthetized rat. Gamma oscillations occur in all subfields, with the highest power in the dentate gyrus.
10.1523/jneurosci.2973-04.2004
29,083,592
Kainate receptors (KARs) play an important role in synaptic physiology, plasticity, and pathological phenomena such as epilepsy. However, the physiological implications for neuronal networks of the distinct expression patterns of KAR subunits are unknown. Using KAR knock-out mice, we show that subunits glutamate recept...
10.1038/nrn2044
Highly detailed analysis of the cellular and molecular mechanisms of kainate-induced gamma oscillations in the hippocampal CA3 region.
10.1046/j.1460-9568.2000.00300.x
20,657,121
Abstract Carbachol (> 20 μ m ) and kainate (100 n m ) induce, in the in vitro CA3 region, synchronized neuronal population oscillations at ≈ 40 Hz having distinctive features: (i) the oscillations persist for hours; (ii) interneurons in kainate fire at 5–20 Hz and their firing is tightly locked to field potential ma...
10.1038/nrn2044
Principal neuron–interneuron model of carbachol-induced gamma oscillations in the CA3 region. In this model, spontaneous EPSCs at principal neuron–interneuron synapses, generated by ectopic action potentials in a network of gap-junction coupled principal neuron axons, have a crucial role.
10.1523/jneurosci.2113-04.2004
80,124,734
Gamma frequency (30-100 Hz) network oscillations occur in the intact hippocampus during awake, attentive behavior. Here, we explored the underlying cellular mechanisms in an in vitro model of persistent gamma-frequency oscillations, induced by bath application of 20 μ m carbachol in submerged hippocampal slices at 30 ±...
10.1038/nrn2044
Whole-cell recording from identified interneuron types during carbachol-induced gamma oscillations in the CA3 subfield in vitro . Various types of interneuron (for example, basket cells and oriens alveus–lacunosum moleculare interneurons) fire at different frequencies and phases.
10.1113/jphysiol.2004.073007
82,696,276
Using whole‐cell patch‐clamp recordings in conjunction with post hoc anatomy we investigated the physiological properties of hippocampal stratum oriens and stratum pyramidale inhibitory interneurones, before and following the induction of pharmacologically evoked gamma frequency network oscillations. Prior to kainate‐i...
10.1038/nrn2044
Whole-cell recording from identified interneuron types during kainate-induced gamma oscillations in the hippocampal CA3 region in vitro . Basket cells fire, on average, 1.2 action potentials per gamma cycle.
10.1523/jneurosci.16-20-06402.1996
20,695,629
Fast neuronal oscillations (gamma, 20–80 Hz) have been observed in the neocortex and hippocampus during behavioral arousal. Using computer simulations, we investigated the hypothesis that such rhythmic activity can emerge in a random network of interconnected GABAergic fast-spiking interneurons. Specific conditions for...
10.1038/nrn2044
A landmark modelling study that systematically examines the conditions under which coherent gamma oscillations are generated in interneuron networks.
10.1523/jneurosci.23-33-10503.2003
67,417,853
Brain rhythms arise through the synchronization of neurons and their entrainment in a regular firing pattern. In this process, networks of reciprocally connected inhibitory neurons are often involved, but what mechanism determines the oscillation frequency is not completely understood. Analytical studies predict that t...
10.1038/nrn2044
Emphasizes the importance of delays (conduction and synaptic) for synchronization in interneuron network models.
10.1162/089976699300016179
125,071,986
We study analytically the dynamics of a network of sparsely connected inhibitory integrate-and-fire neurons in a regime where individual neurons emit spikes irregularly and at a low rate. In the limit when the number of neurons N → ∞, the network exhibits a sharp transition between a stationary and an oscillatory globa...
10.1038/nrn2044
Shows that weak stochastic synchronization occurs in inhibitory interneuron networks if strong coupling is combined with noise. Weak stochastic synchronization differs from strong synchronization in its lower sensitivity to heterogeneities.
10.1073/pnas.192159599
29,332,020
Networks of γ-aminobutyric acid (GABA)ergic interneurons connected via electrical and chemical synapses are thought to play an important role in detecting and promoting synchronous activity in the cerebral cortex. Although the properties of electrical and chemical synaptic interactions among inhibitory interneurons are...
10.1038/nrn2044
Demonstrates fast inhibition at GABA synapses between fast-spiking, parvalbumin-expressing interneurons in the neocortex. Together with similar results obtained in the hippocampus, these results suggest that fast inhibition at basket cell–basket cell synapses is a general phenomenon occurring throughout the cortex.
10.1113/jphysiol.1990.sp018200
41,565,868
1. In simultaneous recordings from pairs of neurones in hippocampal slices from guinea‐pigs, single action potentials fired by CA3 pyramidal cells could initiate inhibitory postsynaptic potentials (IPSPs) in nearby pyramidal cells. 2. The latencies of these IPSPs could be as short as 3 ms. However, they were mediated d...
10.1038/nrn2044
The first paper to show fast and strong synaptic excitation of interneurons by pyramidal cells.
10.1073/pnas.0406343101
59,345,349
Electrical and chemical synapses exist within the same networks of inhibitory cells, and each kind of synapse is known to be able to foster synchrony among oscillating neurons. Using numerical and analytical techniques, we show here that the electrical and inhibitory coupling play different roles in the synchronization...
10.1038/nrn2044
Shows that gap junctions complement inhibitory synapses in the generation of oscillations by permitting the propagation of both suprathreshold and subthreshold potentials.
10.1152/jn.01095.2002
103,743,692
When the local field potential of a cortical network displays coherent fast oscillations (∼40-Hz gamma or ∼200-Hz sharp-wave ripples), the spike trains of constituent neurons are typically irregular and sparse. The dichotomy between rhythmic local field and stochastic spike trains presents a challenge to the theory of ...
10.1038/nrn2044
Simulates the oscillatory activity of a principal neuron–interneuron network in the weak stochastic synchronization regime. The study emphasizes the importance of delays in setting network frequency.
10.1073/pnas.81.14.4586
125,077,847
It is suggested that in the brain the internal attentional searchlight, proposed by Treisman and others, is controlled by the reticular complex of the thalamus (including the closely related perigeniculate nucleus) and that the expression of the searchlight is the production of rapid bursts of firing in a subset of tha...
10.1038/nrn1296
Based, in part, on the results of reference 5, this article presents possible scenarios for the role of bursts in sensory processing.
10.1098/rstb.2002.1154
83,208,005
Thalamic neurons generate high–frequency bursts of action potentials when a low–threshold (T–type) calcium current, located in soma and dendrites, becomes activated. Computational models were used to investigate the bursting properties of thalamic relay and reticular neurons. These two types of thalamic cells differ fu...
10.1038/nrn1296
A modelling study detailing how cortical feedback might differentially affect thalamic relay neurons and thalamic reticular cells.
10.1098/rstb.2002.1170
86,184,467
Thalamic function does not stand apart, as a discrete processing step, from the cortical circuitry. The thalamus receives extensive feedback from the cortex and this influences the firing pattern, synchronization and sensory response mode of relay cells. A crucial question concerns the extent to which the feedback simp...
10.1038/nrn1296
A summary of the authors' studies on the effects of visually driven feedback on thalamic processing.
10.1098/rspb.1981.0039
97,946,455
The activity of visual cortical neurons (area 17) was recorded in anaesthetized cats in response to sinusoidal drifting gratings. The statistical structure of the discharge of simple and complex cells has been studied as a function of the various parameters of a drifting grating: spatial frequency, orientation, driftin...
10.1038/nrn1296
Contains an early analysis correlating bursts to neuronal tuning in complex cells of cat primary visual cortex.
10.1073/pnas.212500599
109,136,906
When images are stabilized on the retina, visual perception fades. During voluntary visual fixation, however, constantly occurring small eye movements, including microsaccades, prevent this fading. We previously showed that microsaccades generated bursty firing in the primary visual cortex (area V-1) in the presence of...
10.1038/nrn1296
A study showing that microsaccade-driven bursts in LGN might indicate stimulus visibility, whereas burst size in V1 neurons might serve as a neural code for stimulus optimality.
10.1126/science.1195870
41,580,065
Internal models of the environment optimize as the brain develops.
10.1038/nrn3687
This work suggests that neural activity in the visual system is the result of the interaction between an internal model of the environment (the prior) and the input from the environment (the posterior), and that the interaction follows a Bayesian rule.
10.1126/science.1129462
62,154,919
Alpha-synuclein (αSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons αSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following αSyn expression in yeast wa...
10.1038/nrn3689
This article uncovers one of the mechanisms explaining why α-synuclein induces ER stress and its relevance to dopaminergic neuron loss.
10.1073/pnas.1002575107
38,397,800
When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requi...
10.1038/nrn3689
This is the first study to demonstrate a role for XBP-1 in ageing through a cell-non-autonomous mechanism.
10.1073/pnas.93.9.3865
18,577,740
The Escherichia coli endoribonuclease RNase E is essential for RNA processing and degradation. Earlier work provided evidence that RNase E exists intracellularly as part of a multicomponent complex and that one of the components of this complex is a 3'-to-5' exoribonuclease, polynucleotide phosphorylase (EC 2.7.7.8). T...
10.1038/nrmicro2930
This study reports the co-purification of RNase E with PNPase, enolase and other proteins. Along with references 24 and 25, this article demonstrates the existence of the RNA degradosome.
10.1111/j.1365-2958.2008.06454.x
26,839,993
Summary RNase E is an essential endoribonuclease involved in RNA processing and mRNA degradation. The N‐terminal half of the protein encompasses the catalytic domain; the C‐terminal half is the scaffold for the assembly of the multienzyme RNA degradosome. Here we identify and characterize ‘segment‐A’, an element in the...
10.1038/nrmicro2930
A demonstration of the basis for membrane binding by RNase E.
10.1101/gad.1127103
62,189,772
RyhB is a small antisense regulatory RNA that is repressed by the Fur repressor and negatively regulates at least six mRNAs encoding Fe-binding or Fe-storage proteins in Escherichia coli . When Fe is limiting, RyhB levels rise, and target mRNAs are rapidly degraded. RyhB is very stable when measured after treatment of ...
10.1038/nrmicro2930
This article and reference 93 link the action of sRNAs to RNase E.