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10.1073/pnas.0708897105
123,065,776
Metagenomics is expanding our knowledge of the gene content, functional significance, and genetic variability in natural microbial communities. Still, there exists limited information concerning the regulation and dynamics of genes in the environment. We report here global analysis of expressed genes in a naturally occ...
10.1038/nrmicro3333
This study, which was conducted at Station ALOHA, is one of the first metatranscriptomic studies of ocean microorganisms and highlights the apparent importance of various phototrophic and chemotrophic pathways of obtaining energy.
10.1073/pnas.1120312109
41,554,663
The atmospheric and deep sea reservoirs of carbon dioxide are linked via physical, chemical, and biological processes. The last of these include photosynthesis, particle settling, and organic matter remineralization, and are collectively termed the “biological carbon pump.” Herein, we present results from a 13-y (1992–...
10.1038/nrmicro3333
Based on a 12 year record of particle flux to the deep sea, this paper documents the coupled interactions between microorganism growth and metabolism in the upper ocean and the flux of material and energy to the deep sea.
10.1126/science.1120250
41,580,238
Microbial life predominates in the ocean, yet little is known about its genomic variability, especially along the depth continuum. We report here genomic analyses of planktonic microbial communities in the North Pacific Subtropical Gyre, from the ocean's surface to near–sea floor depths. Sequence variation in microbial...
10.1038/nrmicro3333
This paper highlights the importance of vertical gradients in the ocean habitat in structuring microbial communities and function using depth-resolved metagenomic sequencing at Station ALOHA.
10.1029/2008gb003418
100,546,691
Dinitrogen (N 2 ) fixing microorganisms (termed diazotrophs) exert important control on the ocean carbon cycle. However, despite increased awareness on the roles of these microorganisms in ocean biogeochemistry and ecology, the processes controlling variability in diazotroph distributions, abundances, and activities re...
10.1038/nrmicro3333
This paper presents a synthesis of multiple data sets from Station ALOHA and a model for the environmental and climate controls on N 2 fixation.
10.1126/science.1165340
26,834,096
Biological nitrogen (N 2 ) fixation is important in controlling biological productivity and carbon flux in the oceans. Unicellular N 2 -fixing cyanobacteria have only recently been discovered and are widely distributed in tropical and subtropical seas. Metagenomic analysis of flow cytometry–sorted cells shows that unic...
10.1038/nrmicro3333
This paper reports the surprising discovery that widely distributed and abundant unicellular N 2 -fixing cyanobacteria lack the genetic capacity for inorganic carbon fixation and oxygen-evolving photosynthesis.
10.4319/lo.1967.12.2.0196
125,070,538
The use of 15 N‐labeled compounds to obtain specific uptake rates for the various nitrogen sources available to the phytoplankton makes it possible to separate the fractions of primary productivity corresponding to new and regenerated nitrogen in the euphotic zone of the ocean. Measurements of nitrate uptake as a fract...
10.1038/nrmicro3333
This paper presents the new production hypothesis that stimulated subsequent field research on nutrient control of primary production.
10.1126/science.1219875
20,477,504
Ocean Methane Is methylphosphonate a natural product? If it is, then its catabolism by microrganisms seeking phosphorus might explain the ubiquity of methane in the oceans. Anaerobic Archaea, so far, are the only significant source of methane known. Thus, Metcalf et al. (p. 1104 ) looked for evidence of methylphosphona...
10.1038/nrmicro3333
This paper describes the genetic pathways underlying the synthesis of methylphosphonic acid by the marine archaeon N. maritimus ; it highlights a potential source of methlyphosphonates to the marine environment and provides support for the hypothesis that the aerobic consumption of methylphosphonates by marine bacteria...
10.1126/science.276.5313.734
62,606,536
Over three decades of molecular-phylogenetic studies, researchers have compiled an increasingly robust map of evolutionary diversification showing that the main diversity of life is microbial, distributed among three primary relatedness groups or domains: Archaea, Bacteria, and Eucarya. The general properties of repres...
10.1038/nrmicro3333
This seminal paper presents a new view of microbial diversity based on cultivation-independent analysis of 16S RNA genes.
10.1073/pnas.98.2.676
125,332,500
A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baselin...
10.1038/nrn2961
The first complete articulation of the idea of a default mode of brain function based on both positron emission tomography (PET) blood flow studies and fMRI. This paper provided the framework for the study of intrinsic activity in neuroimaging.
10.1002/mrm.1910340409
125,327,842
Abstract An MRI time course of 512 echo‐planar images (EPI) in resting human brain obtained every 250 ms reveals fluctuations in signal intensity in each pixel that have a physiologic origin. Regions of the sensorimotor cortex that were activated secondary to hand movement were identified using functional MRI methodolo...
10.1038/nrn2961
This paper demonstrated that brain regions that activate jointly seem to maintain a high correlation of BOLD signal fluctuations at rest, identifying a 'resting-state network' of 'functionally connected' regions. The paper's method of analysis is now known as functional connectivity-by-MRI (fcMRI) or resting-state fMRI...
10.1073/pnas.0135058100
62,607,973
Functional imaging studies have shown that certain brain regions, including posterior cingulate cortex (PCC) and ventral anterior cingulate cortex (vACC), consistently show greater activity during resting states than during cognitive tasks. This finding led to the hypothesis that these regions constitute a network supp...
10.1038/nrn2961
This paper studied for the first time the resting-state connectivity analysis of the default mode and provided clear evidence for the existence of a cohesive default mode network. It also investigated how the default mode network is modulated by task demands and what functions it might serve.
10.1073/pnas.0504136102
20,852,630
During performance of attention-demanding cognitive tasks, certain regions of the brain routinely increase activity, whereas others routinely decrease activity. In this study, we investigate the extent to which this task-related dichotomy is represented intrinsically in the resting human brain through examination of sp...
10.1038/nrn2961
This work was a compelling demonstration of at least two intrinsically coherent networks that could be captured using resting-state fMRI. The work led to the characterization as a task-positive and task-negative network, the latter corresponding to the default mode network
10.1152/jn.90777.2008
41,708,363
Resting state studies of spontaneous fluctuations in the functional MRI (fMRI) blood oxygen level dependent (BOLD) signal have shown great promise in mapping the brain's intrinsic, large-scale functional architecture. An important data preprocessing step used to enhance the quality of these observations has been remova...
10.1038/nrn2961
This paper investigated the anticorrelation between different resting-state networks, showing how the level of anticorrelation is affected by global signal removal. However, the authors demonstrated that several characteristics of anticorrelated networks are not attributable to global signal removal, suggesting that th...
10.1073/pnas.0811168106
20,649,095
In the cerebral cortex, the activity levels of neuronal populations are continuously fluctuating. When neuronal activity, as measured using functional MRI (fMRI), is temporally coherent across 2 populations, those populations are said to be functionally connected. Functional connectivity has previously been shown to co...
10.1038/nrn2961
This paper used computational methods to compare anatomical and fMRI connectivity in humans. The authors concluded that the large-scale anatomical structure of the human cerebral cortex may constrain, but does not entirely account for, the observed global functional connectivity.
10.1073/pnas.0901831106
62,261,954
A growing body of neuroimaging research has documented that, in the absence of an explicit task, the brain shows temporally coherent activity. This so-called “resting state” activity or, more explicitly, the default-mode network, has been associated with daydreaming, free association, stream of consciousness, or inner ...
10.1038/nrn2961
This paper considered that resting-state ultraslow oscillations, and in particular the emergence of anticorrelated subnetworks, result from fluctuation-driven transitions between multistable states. Here, multistable cluster synchronization states appear in coupled oscillator systems owing to the delay of transmission ...
10.1126/science.273.5283.1868
62,058,128
Evoked activity in the mammalian cortex and the resulting behavioral responses exhibit a large variability to repeated presentations of the same stimulus. This study examined whether the variability can be attributed to ongoing activity. Ongoing and evoked spatiotemporal activity patterns in the cat visual cortex were ...
10.1038/nrn2961
This study used optical imaging in the cat visual cortex to characterize the dynamics of spontaneous activity at rest. It showed that the variability of stimulus-evoked activity is largely accounted for by variation in spontaneous activity.
10.1186/gb-2011-12-4-r40
41,317,600
Abstract Background Mycoparasitism, a lifestyle where one fungus is parasitic on another fungus, has special relevance when the prey is a plant pathogen, providing a strategy for biological control of pests for plant protection. Probably, the most studied biocontrol agents are species of the genus Hypocrea / Trichoderm...
10.1038/nrmicro2637
A comparative analysis of the genomes of H. jecorina, H. virens and H. atroviridis , highlighting the gene repertoire that is related to mycoparasitism.
10.1186/1471-2164-10-567
62,237,293
Abstract Background Combating the action of plant pathogenic microorganisms by mycoparasitic fungi has been announced as an attractive biological alternative to the use of chemical fungicides since two decades. The fungal genus Trichoderma includes a high number of taxa which are able to recognize, combat and finally b...
10.1038/nrmicro2637
This study identifies genes that are upregulated in H. atroviridis during its antagonistic interaction with plant-pathogenic fungi.
10.1111/j.1469-8137.2010.03517.x
27,956,973
See also the Commentary by Harman
10.1038/nrmicro2637
This paper shows that H. virens can use plant-derived sucrose.
10.1146/annurev-phyto-073009-114450
125,118,594
Biocontrol fungi (BCF) are agents that control plant diseases. These include the well-known Trichoderma spp. and the recently described Sebacinales spp. They have the ability to control numerous foliar, root, and fruit pathogens and even invertebrates such as nematodes. However, this is only a subset of their abilities...
10.1038/nrmicro2637
This review summarizes how fungi that are used as biocontrol agents stimulate the plant response.
10.1111/j.1364-3703.2007.00430.x
18,321,031
SUMMARY Peptaibols, the products of non‐ribosomal peptide synthetases (NRPS), are linear peptide antibiotics produced by Trichoderma and other fungal genera. Trichoderma virens strain Gv29‐8, a well‐known biocontrol agent and inducer of plant defence responses, produces three lengths of peptaibols, 11, 14 and 18 residu...
10.1038/nrmicro2637
This work demonstrates that peptaibols can induce a plant response.
10.1104/pp.107.103689
81,405,861
Abstract We have previously shown that the beneficial filamentous fungus Trichoderma virens secretes the highly effective hydrophobin-like elicitor Sm1 that induces systemic disease resistance in the dicot cotton (Gossypium hirsutum). In this study we tested whether colonization of roots by T. virens can induce systemi...
10.1038/nrmicro2637
This article describes the stimulation of ISR by a small cysteine-rich protein from H. virens
10.1113/jphysiol.2006.113464
4,614,888
Recent data have substantially advanced our understanding of midbrain dopaminergic neuron development. Firstly, a Wnt1‐regulated genetic network, including Otx2 and Nkx2‐2 , and a Shh‐controlled genetic cascade, including Lmx1a , Msx1 and Nkx6‐1 , have been unravelled, acting in parallel or sequentially to establish a ...
10.1038/nrn2039
In this review, an elegant overview is provided that describes most of the events that are involved in generating mdDA neurons.
10.1126/science.276.5310.248
38,261,392
Dopamine neurons of the substantia nigra and ventral tegmental area regulate movement and affective behavior and degenerate in Parkinson’s disease. The orphan nuclear receptor Nurr1 was shown to be expressed in developing dopamine neurons before the appearance of known phenotypic markers for these cells. Mice lacking N...
10.1038/nrn2039
The first paper to describe the role of NURR1 in the development of mdDA neurons. It was shown later, however, that the 'agenesis' claim is not correct — the early mdDA neurons are born, but are lost as development progresses.
10.1073/pnas.94.24.13305
100,816,569
The mesencephalic dopaminergic (mesDA) system regulates behavior and movement control and has been implicated in psychiatric and affective disorders. We have identified a bicoid-related homeobox gene, Ptx3 , a member of the Ptx -subfamily, that is uniquely expressed in these neurons. Its expression starting at E11.5 in...
10.1038/nrn2039
Here the cloning and identification of Pitx3 is described. These data described the first transcription factor that is exclusively expressed in mdDA neurons and thereby provided a new, unique tool and study object in relation to mdDA neuron development.
10.1073/pnas.91.16.7772
19,279,502
Retinoic acid is synthesized from retinaldehyde by several different dehydrogenases, which are arranged in conserved spatial and developmentally regulated patterns. Here we show for the mouse that a class-1 aldehyde dehydrogenase, characterized by oxidation and disulfiram sensitivity, is found in the brain at high leve...
10.1038/nrn2039
In this paper it was elegantly shown that RALDH1 is present at high levels in mdDA neurons.
10.1083/jcb.200203115
17,592,168
We have previously shown that the neurotrophic effect of glial cell line–derived neurotrophic factor (GDNF) in vitro and in vivo requires the presence of transforming growth factor (TGF)β. Using primary neurons (chick E8 ciliary) we show that the combination of GDNF plus TGFβ promotes survival, whereas the single facto...
10.1038/nrn2039
Describes the crosstalk between TGF signalling and neurotropic support, and thereby provides a new insight into how these two pathways might interact in mdDA neurons.
10.1002/cne.10068
100,438,175
Abstract Diffusible chemorepellents play a major role in guiding developing axons toward their correct targets by preventing them from entering or steering them away from certain regions. Genetic studies in Drosophila revealed a repulsive guidance system that prevents inappropriate axons from crossing the central nervo...
10.1038/nrn2039
The thorough expression analysis of putative guidance factors of mdDA neurons provides an excellent overview that is important in generating a working hypothesis about axon guidance rules that influence mdDA axonal pathfinding.
10.1111/jsr.13598
127,837,473
Summary The two‐process model serves as a major conceptual framework in sleep science. Although dating back more than four decades, it has not lost its relevance for research today. Retracing its origins, I describe how animal experiments aimed at exploring the oscillators driving the circadian sleep–wake rhythm led to...
10.1038/nrn915
The initial presentation of a seminal idea in sleep science that is now supported by electrographic, anatomical and molecular findings (see also references 5 and 22
10.1046/j.0953-816x.2001.01597.x
81,777,246
Abstract The sleep EEG of healthy young men was recorded during baseline and recovery sleep after 40 h of waking. To analyse the EEG topography, power spectra were computed from 27 derivations. Mean power maps of the nonREM sleep EEG were calculated for 1‐Hz bins between 1.0 and 24.75 Hz. Cluster analysis revealed a to...
10.1038/nrn915
An important study showing a frontal predominance of low-frequency EEG rhythms in response to sleep deprivation, which indicates a greater homeostatic need for recovery sleep in the frontal cortex.
10.1111/1467-9280.00306
61,241,407
The exclusion of thinking from recent studies of sleep mentation has hindered a full appreciation of how cognitive activity differs across the states of waking and sleep. To overcome this limitation, this study investigated thoughts and hallucinations using experience sampling, home-based sleep-wake monitoring, and for...
10.1038/nrn915
The demonstration of a reciprocal relationship between thoughts and hallucinatory activity across five distinct behavioural states in a large longitudinal database of the same subjects.
10.1162/089892900562075
20,609,151
Performance on a visual discrimination task shows longterm improvement after a single training session. When tested within 24 hr of training, improvement, was not observed unless subjects obtained at least 6 hr of postraining sleep prior to retesting, in which case improvement was proportional to the amount of sleep in...
10.1038/nrn915
A study showing a correlation of degree of TDT learning with duration of SWS in the first quarter of the night and REM sleep in the last quarter of the night, indicating a two-step process in the sleep-mediated enhancement of TDT learning (see also references 118–122
10.1126/science.1156296
102,308,823
The protozoan parasite Trypanosoma brucei is lysed by apolipoprotein L-I, a component of human high-density lipoprotein (HDL) particles that are also characterized by the presence of haptoglobin-related protein. We report that this process is mediated by a parasite glycoprotein receptor, which binds the haptoglobin-hem...
10.1038/nrmicro3298
This study identifies the parasite surface receptor for both haptoglobin–haemoglobin and TLF1 and provides the first evidence for haem-mediated function in bloodstream form trypanosomes: resistance to oxidative stress from macrophages.
10.1126/science.1114566
62,117,726
Apolipoprotein L-I is the trypanolytic factor of human serum. Here we show that this protein contains a membrane pore-forming domain functionally similar to that of bacterial colicins, flanked by a membrane-addressing domain. In lipid bilayer membranes, apolipoprotein L-I formed anion channels. In Trypanosoma brucei , ...
10.1038/nrmicro3298
This paper characterizes the mechanism of trypanosome lysis by APOL1 and provides the first analysis of the structure and activity of APOLs.
10.1073/pnas.0905669106
15,449,478
Several species of African trypanosomes cause fatal disease in livestock, but most cannot infect humans due to innate trypanosome lytic factors (TLFs). Human TLFs are pore forming high-density lipoprotein (HDL) particles that contain apolipoprotein L-I (apoL-I) the trypanolytic component, and haptoglobin-related protei...
10.1038/nrmicro3298
This study characterizes baboon APOL1, which confers resistance to T. b. rhodesiense
10.1126/science.1193032
103,742,474
Out of Africa Kidney disease is more common in African Americans than in Americans of European descent, and genetics is likely to be a major contributing factor. Genovese et al. (p. 841 , published online 15 July) now show that African Americans who carry specific sequence variants in a gene on chromosome 22 encoding a...
10.1038/nrmicro3298
This paper shows that natural human APOL1 variants provide resistance to T. b. rhodesiense and provides evidence for the association of these variants with kidney disease.
10.1523/jneurosci.3427-09.2010
19,234,366
Synapses maintain synchronous, asynchronous, and spontaneous forms of neurotransmission that are distinguished by their Ca 2+ dependence and time course. Despite recent advances in our understanding of the mechanisms that underlie these three forms of release, it remains unclear whether they originate from the same ves...
10.1038/nrn3875
This paper suggests that both synchronous- and asynchronous-evoked release originate from a pool of vesicles that recycles rapidly in a dynamin-dependent manner, whereas vesicles released spontaneously are derived from a separate pool that does not require dynamin for recycling.
10.1523/jneurosci.2432-08.2008
104,416,147
In a synapse, spontaneous and action-potential-driven neurotransmitter release is assumed to activate the same set of postsynaptic receptors. Here, we tested this assumption using (+)-5-methyl-10,11-dihydro-5 H -dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), a well characterized use-dependent blocker of NMDA re...
10.1038/nrn3875
This study takes advantage of the use-dependent NMDA receptor antagonist MK-801 and uses electrophysiology to demonstrate that glutamate released spontaneously or as a result of action potential stimulation activates different populations of NMDA receptors. These observations are supported by imaging of both spontaneou...
10.1073/pnas.0709067105
78,060,674
Synaptic vesicles release neurotransmitter by following a process of vesicle docking and exocytosis. Although these steps are well established, it has been difficult to observe and measure these rates directly in living synapses. Here, by combining the direct imaging of single synaptic vesicles and synaptic ribbons, I ...
10.1038/nrn3875
This paper provides evidence for the spatial segregation of different types of neurotransmission using single-vesicle imaging of goldfish bipolar cell ribbon synapses. Vesicles released as a result of stimulation are predominantly localized to the ribbon, whereas spontaneous release often occurs at extra-ribbon sites.
10.1523/jneurosci.3334-13.2013
83,499,686
Neurotransmitter release from synaptic vesicle fusion is the fundamental mechanism for neuronal communication at synapses. Evoked release following an action potential has been well characterized for its function in activating the postsynaptic cell, but the significance of spontaneous release is less clear. Using trans...
10.1038/nrn3875
This study uses transgenic expression of GCAMP5 at the D. melanogaster neuromuscular junction and detected unitary spontaneous and action potential-evoked postsynaptic Ca 2+ transients. In most synaptic spots, coexistence of spontaneous and evoked signals was observed. However, approximately 22% of all synaptic regions...
10.1083/jcb.99.6.2041
38,595,481
To examine the role in neurite growth of actin-mediated tensions within growth cones, we cultured chick embryo dorsal root ganglion cells on various substrata in the presence of cytochalasin B. Time-lapse video recording was used to monitor behaviors of living cells, and cytoskeletal arrangements in neurites were asses...
10.1038/nrn2236
This was the first study to demonstrate that actin superstructures are dispensable for neurite elongation.
10.1073/pnas.96.9.4908
60,243,950
Actin polymerization is required for the generation of motile force at the leading edge of both lamellipodia and filopodia and also at the surface of motile intracellular bacterial pathogens such as Listeria monocytogenes . Local catalysis of actin filament polymerization is accomplished in L. monocytogenes by the bact...
10.1038/nrn2236
This paper, together with reference 11, reported the complete reconstitution of L. monocytogenes actin-based comet-tail motility using a cell-free system, demonstrating that a force-producing actin-based machine could be assembled without external signalling or motor proteins.
10.1083/jcb.107.4.1505
40,548,215
Actions of cytochalasin B (CB) on cytoskeletons and motility of growth cones from cultured Aplysia neurons were studied using a rapid flow perfusion chamber and digital video light microscopy. Living growth cones were observed using differential interference contrast optics and were also fixed at various time points to...
10.1038/nrn2236
By reversibly blocking actin assembly, this study demonstrated that growth-cone actin superstructures are assembled de novo at the leading edge.
10.1083/jcb.200703055
123,611,461
Bone morphogenic proteins (BMPs) are involved in axon pathfinding, but how they guide growth cones remains elusive. In this study, we report that a BMP7 gradient elicits bidirectional turning responses from nerve growth cones by acting through LIM kinase (LIMK) and Slingshot (SSH) phosphatase to regulate actin-depolyme...
10.1038/nrn2236
The results in this paper stand alone in demonstrating that the bidirectional regulation of a single type of actin-binding protein can mediate both attractive and repulsive turning in response to the same extracellular guidance cue.
10.1126/science.1100533
20,522,723
Cell migration initiates by extension of the actin cytoskeleton at the leading edge. Computational analysis of fluorescent speckle microscopy movies of migrating epithelial cells revealed this process is mediated by two spatially colocalized but kinematically, kinetically, molecularly, and functionally distinct actin n...
10.1038/nrn2236
This study used FSM to identify two populations of actin speckles that correspond to actin subunits from lamellipodia and lamellae.
10.1091/mbc.e02-04-0244
45,302,505
The specific functions of greater than 40 vertebrate nonmuscle tropomyosins (Tms) are poorly understood. In this article we have tested the ability of two Tm isoforms, TmBr3 and the human homologue of Tm5 (hTM5 NM1 ), to regulate actin filament function. We found that these Tms can differentially alter actin filament o...
10.1038/nrn2236
This study was the first to demonstrate that both competitive and synergistic interactions between different tropomyosin isoforms and ADF/cofilin regulate binding to different actin-filament populations.
10.1073/pnas.79.2.490
122,221,237
Free microtubule or actin filaments, along with the monomeric forms of the protein, hydrolyze GTP or ATP to produce a flux of subunits through the polymer. This flux, called treadmilling, produces no useful work. In the cell, however, these filaments are likely to be constrained between nucleating sites and other barri...
10.1038/nrn2236
This seminal paper provided the theoretical basis for the concept that cytoskeleton proteins can function as 'molecular machines' owing to their ability to treadmill — a concept that has proven integral to current models of actin-based motility.
10.1111/j.1365-2869.2004.00429.x
124,323,508
Summary The study purpose was to assess inter‐ and intra‐individual variability in neurobehavioral function near the circadian nadir during sleep deprivation and conduct exploratory factor analyses to assess relationships among alertness and performance measures during sleep deprivation. Twenty‐five healthy individuals...
10.1038/nrn.2017.55
This study characterizes the variability in behavioural performance across several task domains in response to SD, both within and between individuals.
10.1146/annurev.neuro.31.060407.125536
20,703,889
Neurons are among the most highly polarized cell types in the body, and the polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. Significant progress has been made in the identification of the cellular and molecular mechanisms underlying the establishme...
10.1038/nrn2852
This excellent review provides a broad overview of the developmental mechanisms underlying the establishment of neuronal polarity.
10.1083/jcb.200805169
47,785,714
In neurons, generation and propagation of action potentials requires the precise accumulation of sodium channels at the axonal initial segment (AIS) and in the nodes of Ranvier through ankyrin G scaffolding. We found that the ankyrin-binding motif of Nav1.2 that determines channel concentration at the AIS depends on a ...
10.1038/nrn2852
This paper showed that phosphorylation of Na + channels by CSNK2 increases Na + channel affinity for AnkG at nodes and the AIS. It also suggests that the density of channels at the AIS and nodes could by regulated by phosphorylation.
10.1083/jcb.143.5.1295
103,776,817
Voltage-gated sodium channels (NaCh) are colocalized with isoforms of the membrane-skeletal protein ankyrinG at axon initial segments, nodes of Ranvier, and postsynaptic folds of the mammalian neuromuscular junction. The role of ankyrinG in directing NaCh localization to axon initial segments was evaluated by region-sp...
10.1038/nrn2852
This paper was the first to show that AnkG is required for Na + channel clustering at the AIS.
10.1083/jcb.200806112
20,611,542
The axon initial segment (AIS) functions as both a physiological and physical bridge between somatodendritic and axonal domains. Given its unique molecular composition, location, and physiology, the AIS is thought to maintain neuronal polarity. To identify the molecular basis of this AIS property, we used adenovirus-me...
10.1038/nrn2852
This paper was the first to demonstrate that the AIS diffusion barrier and maintenance of neuronal polarity depend on AnkG.
10.1073/pnas.172501299
39,888,485
Streptococcus mutans is the leading cause of dental caries (tooth decay) worldwide and is considered to be the most cariogenic of all of the oral streptococci. The genome of S. mutans UA159, a serotype c strain, has been completely sequenced and is composed of 2,030,936 base pairs. It contains 1,963 ORFs, 63% of which ...
10.1038/nrmicro771
Contains a description of the S. mutans genome and an analysis of metabolic and regulatory aspects revealed by the genomic sequence.
10.1046/j.1365-2958.2002.03126.x
125,166,128
Summary Streptococcus agalactiae is a commensal bacterium colonizing the intestinal tract of a significant proportion of the human population. However, it is also a pathogen which is the leading cause of invasive infections in neonates and causes septicaemia, meningitis and pneumonia. We sequenced the genome of the ser...
10.1038/nrmicro771
This paper and reference 147 describe the genome sequence of GBS, giving details of genomic structure, comparative genomics and metabolic insights from the two strains sequenced.
10.1126/science.1061217
83,050,158
The 2,160,837–base pair genome sequence of an isolate of Streptococcus pneumoniae , a Gram-positive pathogen that causes pneumonia, bacteremia, meningitis, and otitis media, contains 2236 predicted coding regions; of these, 1440 (64%) were assigned a biological role. Approximately 5% of the genome is composed of insert...
10.1038/nrmicro771
Highlights the differences between the stains and shows the ability of the organism to transport many sugars.
10.1073/pnas.062526099
61,759,883
Acute rheumatic fever (ARF), a sequelae of group A Streptococcus (GAS) infection, is the most common cause of preventable childhood heart disease worldwide. The molecular basis of ARF and the subsequent rheumatic heart disease are poorly understood. Serotype M18 GAS strains have been associated for decades with ARF out...
10.1038/nrmicro771
This paper and references 148, 149 and 150 describe the genome sequences of four strains of GAS. These studies describe the genomic organization of the strains, microarray analysis of strains associated with acute rheumatic fever, and provide an insight into the role of phages and genomic rearrangements in virulence.
10.1073/pnas.0337370100
81,660,951
Group A Streptococcus (GAS) evades polymorphonuclear leukocyte (PMN) phagocytosis and killing to cause human disease, including pharyngitis and necrotizing fasciitis (flesh-eating syndrome). We show that GAS genes differentially regulated during phagocytic interaction with human PMNs comprise a global pathogen-protecti...
10.1038/nrmicro771
Analysis of genome-wide gene-expression changes on interaction of GAS with human polymorphonuclear cells. Confirmation of the role of a two-component system in virulence and that this system is upregulated during human infection.
10.1073/pnas.202353699
20,424,169
Two-component gene regulatory systems composed of a membrane-bound sensor and cytoplasmic response regulator are important mechanisms used by bacteria to sense and respond to environmental stimuli. Group A Streptococcus , the causative agent of mild infections and life-threatening invasive diseases, produces many virul...
10.1038/nrmicro771
Global expression profiling in GAS using microarrays to examine the control of virulence gene expression.
10.1073/pnas.0711697105
104,041,813
The persistence of Mycobacterium tuberculosis despite prolonged chemotherapy represents a major obstacle for the control of tuberculosis. The mechanisms used by Mtb to persist in a quiescent state are largely unknown. Chemical genetic and genetic approaches were used here to study the physiology of hypoxic nonreplicati...
10.1038/nrmicro2474
This research can be considered a landmark achievement; it demonstrates the importance of the proton motive force in M. tuberculosis and shows why dormant M. tuberculosis is killed by agents that affect this property.
10.1146/annurev.micro.112408.134306
41,669,588
Persisters are dormant variants of regular cells that form stochastically in microbial populations and are highly tolerant to antibiotics. High persister (hip) mutants of Pseudomonas aeruginosa are selected in patients with cystic fibrosis. Similarly, hip mutants of Candida albicans are selected in patients with an ora...
10.1038/nrmicro2474
This article describes the search for persister genes and findings indicating that multiple genes or pathways are involved.
10.1126/science.1106753
103,845,451
The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (min...
10.1038/nrmicro2474
This landmark work describes the discovery of the novel drug TMC207.
10.1046/j.1460-9568.2003.02608.x
87,249,136
Abstract Exposure to a novel taste solution in the rat is followed by a decrease in its intake known as neophobia. This effect gradually disappears, and consumption increases from the second presentation of the taste (attenuation of neophobia), reflecting that the animal learned that it is safe to drink it. Conversely,...
10.1038/nrn1344
Shows that, although cortical muscarinic receptors are important in the formation and consolidation of safe memory trace, NMDA-receptor activity seems to be less relevant.
10.1101/lm.6.1.37
133,942,889
Short-term memory is a rapid, labile, and protein-synthesis-independent phase of memory. The existence of short-term memory in conditioned taste aversion (CTA) learning has not been demonstrated formally. To determine the earliest time at which a CTA is expressed, we measured intraoral intake of sucrose at 15 min, 1 hr...
10.1038/nrn1344
Shows that central administration of a protein-synthesis inhibitor before injection of lithium chloride blocked long-term, but not short-term, CTA expression.
10.1046/j.0953-816x.2001.01631.x
106,951,501
Abstract There is strong evidence that decrements in neuronal activation in perirhinal cortex when a novel stimulus is repeated provide a neural substrate of visual recognition memory. There is also strong evidence that muscarinic acetylcholine (ACh) receptors are involved in learning and memory. However, the mechanism...
10.1038/nrn1344
Describes that perirhinal cortex activation of ACh receptors in vitro produces long-lasting depression of synaptic transmission that is dependent on muscarinic M1, but not on NMDA receptor activation.
10.1101/gr.116335.110
122,273,512
RNA-sequencing (RNA-seq) allows quantitative measurement of expression levels of genes and their transcripts. In this study, we sequenced complementary DNA fragments of cultured human B-cells and obtained 879 million 50-bp reads comprising 44 Gb of sequence. The results allowed us to study the gene expression profile o...
10.1038/nrmicro2852
An in-depth transcriptomic study on human B cells that defines the coverage requirements for different biological applications such as gene discovery and expression quantification.
10.1101/gr.124321.111
62,291,443
Next-generation sequencing (NGS) technologies are revolutionizing genome research, and in particular, their application to transcriptomics (RNA-seq) is increasingly being used for gene expression profiling as a replacement for microarrays. However, the properties of RNA-seq data have not been yet fully established, and...
10.1038/nrmicro2852
An exploration of the sequencing depths that are required for accurate gene expression profiling in mammals.
10.1101/gr.116103.110
18,921,788
Total transcript amplification (TTA) from single eukaryotic cells for transcriptome analysis is established, but TTA from a single prokaryotic cell presents additional challenges with much less starting material, the lack of poly(A)-tails, and the fact that the messages can be polycistronic. Here, we describe a novel m...
10.1038/nrmicro2852
The first study to monitor differential gene expression in a single bacterial cell by Sanger sequencing.
10.1111/1467-9280.00117
59,320,890
Participants named objects presented in the left or right visual field during a test phase, after viewing centrally presented same-exemplar objects, different-exemplar objects, and words that name objects during an initial encoding phase. In two experiments, repetition priming was exemplar-abstract yet visual when test...
10.1038/nrn1364
Provides empirical support for a dual systems theory of object recognition that includes an abstract subsystem for categorization in the left hemisphere and an exemplar-specific subsystem for individuation in the right hemisphere.
10.1162/089892902317236830
65,250,762
We investigated the influence of a categorization task on the extraction and representation of perceptual features in humans and monkeys. The use of parameterized stimuli (schematic faces and fish) with fixed diagnostic features in combination with a similarity-rating task allowed us to demonstrate perceptual sensitiza...
10.1038/nrn1364
Monkeys and humans learned novel object categories with feedback. Comparative fits of computational models to observed response probabilities indicated that neither monkeys nor humans learned categories by abstracting a prototype, but instead based categorization decisions either on similarity to exemplars or with resp...
10.1111/1467-9280.00207
41,040,102
In an attempt to reconcile results of previous studies, several theorists have suggested that object recognition performance should range from viewpoint invariant to highly viewpoint dependent depending on how easy it is to differentiate the objects in a given recognition situation. The present study assessed recogniti...
10.1038/nrn1364
Refutes a common prediction that object recognition should be viewpoint-invariant when an object set is highly discriminable. The results support the notion that differences in object geometry are more important than the difficulty of the categorization in terms of accounting for viewpoint effects.
10.1111/1467-9280.00308
122,805,491
Although most adults are considered to be experts in the identification of faces, fewer people specialize in the recognition of other objects, such as birds and dogs. In this research, the neurophysiological processes associated with expert bird and dog recognition were investigated using event-related potentials. An e...
10.1038/nrn1364
The first ERP study to provide evidence for expertise effects (with dog and bird images) on the N170 face-selective potential.
10.1073/pnas.96.15.8779
17,678,837
Phototropism, the bending response of plant organs to or away from a directional light source, is one of the best studied blue light responses in plants. Although phototropism has been studied for more than a century, recent advances have improved our understanding of the underlying signaling mechanisms involved. The N...
10.1038/nrmicro2622
First report that LOV domains contain a non-covalently bound flavin cofactor.
10.1128/mmbr.63.2.479-506.1999
62,385,664
SUMMARY PAS domains are newly recognized signaling domains that are widely distributed in proteins from members of the Archaea and Bacteria and from fungi, plants, insects, and vertebrates. They function as input modules in proteins that sense oxygen, redox potential, light, and some other stimuli. Specificity in sensi...
10.1038/nrmicro2622
A classic review that firmly establishes the importance of PAS domains in the regulation of a range of physiological processes in bacteria.
10.1073/pnas.0705887104
18,821,061
Flavin-binding LOV domains are blue-light photosensory modules that are conserved in a number of developmental and circadian regulatory proteins in plants, algae, and fungi. LOV domains are also present in bacterial genomes, and are commonly located at the amino termini of sensor histidine kinases. Genes predicted to e...
10.1038/nrmicro2622
This work demonstrates a role of the LovK–LovR photosensory two-component system in the regulation of cell adhesion in Caulobacter spp.
10.1126/science.1144306
62,079,155
Histidine kinases, used for environmental sensing by bacterial two-component systems, are involved in regulation of bacterial gene expression, chemotaxis, phototaxis, and virulence. Flavin-containing domains function as light-sensory modules in plant and algal phototropins and in fungal blue-light receptors. We have di...
10.1038/nrmicro2622
This article reports the surprising discovery that visible light, via a LOV HK, regulates the virulence of Brucella spp. in a macrophage infection model.
10.1073/pnas.051520298
80,223,568
Phototropin, a major blue-light receptor for phototropism in seed plants, exhibits blue-light-dependent autophosphorylation and contains two light, oxygen, or voltage (LOV) domains and a serine/threonine kinase domain. The LOV domains share homology with the PER-ARNT-SIM (PAS) superfamily, a diverse group of sensor pro...
10.1038/nrmicro2622
The first report of the molecular structure of the LOV domain bound to its flavin cofactor.
10.1126/science.1086810
83,121,671
Phototropins are light-activated kinases important for plant responses to blue light. Light initiates signaling in these proteins by generating a covalent protein–flavin mononucleotide (FMN) adduct within sensory Per-ARNT-Sim (PAS) domains. We characterized the light-dependent changes of a phototropin PAS domain by sol...
10.1038/nrmicro2622
This study elucidates the large-scale structural change that occurs in the C-terminal Jα helix upon light absorption by the LOV domain.
10.1073/pnas.0709610105
41,360,734
An understanding of how allostery, the conformational coupling of distant functional sites, arises in highly evolvable systems is of considerable interest in areas ranging from cell biology to protein design and signaling networks. We reasoned that the rigidity and defined geometry of an α-helical domain linker would m...
10.1038/nrmicro2622
This work shows that the addition of a LOV domain can modulate the activity of the Escherichia coli tryptophan repressor.
10.1523/jneurosci.15-04-02638.1995
19,248,065
Physiological and morphological properties of nonpyramidal cells in layer II/III of frontal cortex of young rats were studied in vitro by whole-cell recording and intracellular staining with biocytin. Layer II/III nonpyramidal cells could be divided into four subgroups by their firing patterns in response to depolarizi...
10.1038/nrn1648
The first report that correlated electrophysiological and morphological features of cortical GABA neurons.
10.1523/jneurosci.23-15-06315.2003
62,596,972
Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothes...
10.1038/nrn1648
Through the use of subpopulation-specific molecular markers, this study confirmed that the parvalbumin-expressing subpopulation of GABA neurons is particularly vulnerable in schizophrenia.
10.1126/science.1060342
82,275,249
The temporal resolution of neuronal integration depends on the time window within which excitatory inputs summate to reach the threshold for spike generation. Here, we show that in rat hippocampal pyramidal cells this window is very narrow (less than 2 milliseconds). This narrowness results from the short delay with wh...
10.1038/nrn1648
An important investigation that shows the role of feedforward perisomatic inhibition in controlling the timing of pyramidal cell function.
10.1126/science.7678183
62,665,850
Tumor necrosis factor-α (TNF-α) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-α messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-α protein was also elevated locally and systemically. Neutralizati...
10.1038/nrrheum.2016.209
This paper demonstrated for the first time that white adipose tissue is an active metabolic tissue rather than a mere fat depot.
10.1002/art.10811
60,012,015
Abstract Objective To study, in vitro, the effect of leptin (OB), alone or in combination with interferon‐γ (IFNγ), on inducible nitric oxide synthase (iNOS) and NO production in human primary chondrocytes and in mouse embryonic chondrogenic ATDC5 cells. Methods Leptin receptor expression and iNOS messenger RNA express...
10.1038/nrrheum.2016.209
This is the first published evidence of the activity of leptin in the regulation of inflammatory response in human and mouse chondrocytes.
10.1136/ard.2010.132399
123,563,503
Background Obesity is a major risk factor for a plethora of diseases including joint disorders associated with cartilage destruction. Recently, it has been demonstrated that adipose tissue might contribute to degenerative joint diseases via the secretion of potent bioactive molecules termed adipokines. Objective To stu...
10.1038/nrrheum.2016.209
This article described for the first time the expression of a novel network of adipokines locally produced in human and mouse cartilage.
10.1073/pnas.1214554110
111,114,526
Leptin is an adipocyte-derived hormone that controls food intake and reproductive and immune functions in rodents. In uncontrolled human studies, low leptin levels are associated with impaired immune responses and reduced T-cell counts; however, the effects of leptin replacement on the adaptive immune system have not y...
10.1038/nrrheum.2016.209
This is a relevant article demonstrating important pharmacological properties of leptin in modulating immune response
10.1523/jneurosci.23-22-07981.2003
123,856,414
Protons are the most ubiquitous and very potent modulators of the biological systems. Hydrogen ions are known to modulate GABA A receptors (GABA A Rs), but the mechanism whereby these ions affect IPSCs and the gating of GABA A Rs is not clear. In the present study we examined the effect of protons on miniature IPSCs (m...
10.1038/nrn1625
The authors investigated the properties of mIPSCs at various pH values, and, from responses to exogenous GABA, separately determined that protons affect the binding and desensitization of GABA A receptors. By modelling mIPSCs as responses to exponentially decaying GABA concentration transients, they were able to reprod...
10.1113/jphysiol.1996.sp021806
124,941,315
1. To investigate the origin and functional significance of a recently described tonic GABAA receptor‐mediated conductance in cerebellar granule cells we have made recordings from cells in cerebellar slices from rats of different ages (postnatal days P4 to P28). 2. During development there was a dramatic change in the ...
10.1038/nrn1625
The authors investigated the postnatal development and inhibitory effects of the tonic GABA A receptor-mediated conductance in cerebellar granule cells. This was first identified in reference 41 and was shown to be distinct from the superimposition of phasic synaptic events. The conductance was found to increase with a...
10.1126/science.1060342
82,275,249
The temporal resolution of neuronal integration depends on the time window within which excitatory inputs summate to reach the threshold for spike generation. Here, we show that in rat hippocampal pyramidal cells this window is very narrow (less than 2 milliseconds). This narrowness results from the short delay with wh...
10.1038/nrn1625
Shows, in hippocampal pyramidal cells, how the disynaptic feed-forward inhibition that follows monosynaptic excitation substantially restricts the window in which temporal summation can occur. Regional differences in the strength of inhibition allow the dendrites to integrate input over a broad time window while enforc...
10.1073/pnas.2435457100
104,308,890
Neuroactive steroids are potent modulators of γ-aminobutyric acid type A receptors (GABA A Rs), and their behavioral effects are generally viewed in terms of altered inhibitory synaptic transmission. Here we report that, at concentrations known to occur in vivo , neuroactive steroids specifically enhance a tonic inhibi...
10.1038/nrn1625
Showed that, in granule cells of the dentate gyrus and cerebellum, the neurosteroid THDOC, at a low concentration that is known to occur in vivo , specifically enhanced the tonic inhibitory conductance that was mediated by extrasynaptic δ-subunit-containing GABA A receptors.
10.1073/pnas.0307231101
19,431,904
The principal inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA), is thought to regulate memory processes by activating transient inhibitory postsynaptic currents. Here we describe a nonsynaptic, tonic form of inhibition in mouse CA1 pyramidal neurons that is generated by a distinct subpopul...
10.1038/nrn1625
By recording from hippocampal slices previously incubated in the GABA transaminase blocker vigabatrin, the authors showed that the tonic GABA A receptor-mediated conductance in CA1 pyramidal neurons was reduced in cells from mice that lacked the α5 subunit of the GABA A receptor.
10.1523/jneurosci.09-06-02197.1989
32,899,795
Two monoclonal antibodies, bd-17 and bd-24, specific for the beta- and alpha-subunit of the GABAA/benzodiazepine receptor/chloride channel complex, respectively, were used to determine the subcellular distribution of immunoreactivity in the cerebellum by electron microscopy. The 2 antibodies showed similar antigen dist...
10.1038/nrn1625
The first high-resolution demonstration of the presence of non-synaptic GABA A receptors on the surface of CNS neurons.
10.1523/jneurosci.15-04-02948.1995
67,422,463
Ion channels gated by the inhibitory neurotransmitter gamma- aminobutyric acid (GABA) are thought to be located in synaptic junctions, but they have also been found throughout the somatodendritic membrane of neurons independent of synapses. To test whether synaptic junctions are enriched in GABAA receptors, and to dete...
10.1038/nrn1625
Showed that in cerebellar granule cells, the total number of extrasynaptic GABA A receptors exceeds that in GABA-releasing synapses.
10.1523/jneurosci.18-05-01693.1998
41,294,355
Two types of GABA A receptor-mediated inhibition (phasic and tonic) have been described in cerebellar granule cells, although these cells receive GABAergic input only from a single cell type, the Golgi cell. In adult rats, granule cells express six GABA A receptor subunits abundantly (α1, α6, β2, β3, γ2, and δ), which ...
10.1038/nrn1625
A demonstration, using immunogold electron microscopy, of the exclusively extrasynaptic presence of the δ subunit in cerebellar granule cells.
10.1073/pnas.2435171100
104,182,421
γ-Aminobutyric acid type A receptors (GABARs) have long been implicated in mediating ethanol (EtOH) actions, but so far most of the reported recombinant GABAR combinations have shown EtOH responses only at fairly high concentrations (≥60 mM). We show that GABARs containing the δ-subunit, which are highly sensitive to γ...
10.1038/nrn1625
References 174 and 175 provide an elegant demonstration that concentrations of ethanol that can be reached with moderate, social alcohol consumption enhance responses from δ but not γ2 subunit-containing GABA A receptors.
10.1002/cne.902240408
102,920,754
Abstract The cortical representations of the hand in area 3b in adult owl monkeys were defined with use of microelectrode mapping techniques 2–8 months after surgical amputation of digit 3, or of both digits 2 and 3. Digital nerves were tied to prevent their regeneration within the amputation stump. Successive maps wer...
10.1038/nrn754
A classic paper that showed injury-related cortical reorganization in monkeys.
10.1146/annurev.neuro.21.1.149
104,427,233
▪ Abstract It has been clear for almost two decades that cortical representations in adult animals are not fixed entities, but rather, are dynamic and are continuously modified by experience. The cortex can preferentially allocate area to represent the particular peripheral input sources that are proportionally most us...
10.1038/nrn754
Reviews much of the literature on cortical reorganization, particularly that in animals.
10.1126/science.272.5269.1791
83,012,323
Substantial functional reorganization takes place in the motor cortex of adult primates after a focal ischemic infarct, as might occur in stroke. A subtotal lesion confined to a small portion of the representation of one hand was previously shown to result in a further loss of hand territory in the adjacent, undamaged ...
10.1038/nrn754
Shows that a CI-therapy-like procedure in monkeys produces plastic alteration in the organization and function of the brain, which correlates with the rehabilitative effects of the intervention. A similar phenomenon was shown for the use of CI therapy after stroke in humans (references 35–38
10.1161/01.str.32.7.1621
107,301,421
Abstract —Patients with chronic aphasia were assigned randomly to a group to receive either conventional aphasia therapy or constraint-induced (CI) aphasia therapy, a new therapeutic technique requiring intense practice over a relatively short period of consecutive days. CI aphasia therapy is realized in a communicativ...
10.1038/nrn754
Describes a successful extension of CI therapy to treating speech impairments after stroke.
10.1126/science.271.5245.77
62,666,442
Children with language-based learning impairments (LLIs) have major deficits in their recognition of some rapidly successive phonetic elements and nonspeech sound stimuli. In the current study, LLI children were engaged in adaptive training exercises mounted as computer “games” designed to drive improvements in their “...
10.1038/nrn754
This and the following paper describe the extension of basic research on cortical reorganization in animals and the mechanism of SLI in humans to the development of Fast ForWord, an effective intervention for the remediation of SLI and dyslexia.
10.1161/01.str.28.6.1225
82,289,887
Background and Purpose The purpose of this study was to evaluate whether grafting of fetal neocortical tissue 1 week after focal brain ischemia improved behavioral outcome and reduced secondary thalamic atrophy. Methods One week after distal ligation of the right middle cerebral artery in spontaneously hypertensive mal...
10.1038/nrn754
An enriched environment improved the behavioural outcome of neural grafting after brain damage in rats. This raises the question of whether this approach might have relevance to humans.