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10.1002/cne.902950407
124,244,511
Abstract The distribution of intrahippocampal projections arising from the CA3 region of the rat hippocampus was investigated using in vitro and in vivo methods. In the in vitro hippocampal slice preparation, single CA3 pyramidal cells were intracellularly labeled with horseradish peroxidase (HRP), and the three‐dimens...
10.1038/nrn.2016.87
References 81 and 82 showed that there was a pattern of innervation 'back' to the dentate gyrus, opposite to the direction of the trisynaptic circuitry.
10.1152/jn.1994.72.5.2167
17,277,154
1. Simultaneous intracellular recordings of area CA3 pyramidal cells and dentate hilar “mossy” cells were made in rat hippocampal slices to test the hypothesis that area CA3 pyramidal cells excite mossy cells monosynaptically. Mossy cells and pyramidal cells were differentiated by location and electrophysiological char...
10.1038/nrn.2016.87
References 83 and 84 showed the physiological effects that supported the idea that pyramidal cells innervate hilar neurons such as mossy cells.
10.1126/science.6801762
20,856,776
After infection and a prolonged incubation period, the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Six lines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that is required for infectivity. Although the scrapie agent is irr...
10.1038/nrn3887
A landmark publication that defines prions as infectious proteinaceous particles.
10.1111/j.1749-6632.1993.tb23057.x
107,327,609
Moderate numbers of amyloid plaques with associated argyrophilic dystrophic neurites and cerebral amyloid angiopathy (CAA) but no neurofibrillary tangles (NFTs) were found in the brains of 3 middle‐aged common marmosets ( Callithrix jacchus ) inoculated intracerebrally (i.e.) 6–7 years earlier with brain tissue from a ...
10.1038/nrn3887
This paper provides evidence that senile plaques in the brains of nonhuman primates can be induced by the intracerebral injection of human AD brain homogenates.
10.1126/science.1227157
20,881,057
Synthetic Parkinson's Parkinson's disease (PD) and related α-synucleinopathies are defined by the accumulation of α-synuclein (α-Syn)–containing intraneuronal inclusions—Lewy bodies (LBs) and Lewy neurites (LNs)—in association with the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and other ...
10.1038/nrn3887
This report describes the induction of α-synuclein pathology by the intracerebral injection of synthetic α-synuclein fibrils into non-transgenic mice.
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/nrn3887
The study describes the development of 11 C-PiB, which is currently the most widely used PET tracer for Aβ.
10.1126/science.1194516
80,294,455
Infectious Amyloid? Patients with Alzheimer's disease have characteristic lesions in the brains associated with masses of polymerized protein called β-amyloid. Recently, evidence from mouse models of Alzheimer's disease shows that brain extracts containing β-amyloid can “infect” otherwise healthy animals when injected ...
10.1038/nrn3887
This study shows that cerebral Aβ pathology can be caused by the introduction of Aβ seeds into the peritoneum.
10.1192/bjp.bp.105.018150
19,079,637
Summary The ability to recognise fear is impaired in people with damage to the amygdala and, interestingly, in adult psychopathy. Here we confirm that deficits in recognising fear exist in children with psychopathic traits. We show for the first time that, as with patients with amygdala damage, this deficit can be temp...
10.1038/nrn3577
An important study documenting that the impairment in the recognition of fearful expressions seen in youths with callous–unemotional traits is significantly reduced when the participant's attention is directed to the eye region of the face. This improvement is also seen in patients with amygdala lesions.
10.1111/j.1469-7610.2004.00393.x
103,731,676
Background: Individuals with early warning signs of life‐long psychopathy, callous‐unemotional traits (CU) and high levels of antisocial behaviour (AB) can be identified in childhood. We report here the first twin study of high levels of psychopathic tendencies in young children. Methods: At the end of the first school...
10.1038/nrn3577
One of the first studies to document the high heritability of callous–unemotional traits in youths.
10.1126/science.1079469
41,472,028
Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Aβ peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The ...
10.1038/nrn1587
This study shows that spherical oligomers formed by several distinct amyloidogenic proteins share a common structural epitope that is recognized by an oligomer-specific antibody.
10.1073/pnas.242720499
40,659,069
Molecular chaperones and their functions in protein folding have been implicated in several neurodegenerative diseases, including Parkinson's disease and Huntington's disease, which are characterized by accumulation of protein aggregates (e.g., α-synuclein and huntingtin, respectively). These aggregates have been shown...
10.1038/nrn1587
In this study, both RNAi and drug-induced chaperone overexpression were used to show that HSP70 and HSP90 chaperones maintain tau in a soluble, functional conformation and concomitantly prevent tau aggregation.
10.1126/science.1067389
107,397,480
Parkinson's disease is a movement disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic neuronal loss also occurs in Drosophila melanogaster upon directed expression of α-synuclein, a protein implicated in the pathogenesis of Parkinson's disease and a major c...
10.1038/nrn1587
The first study to show a neuroprotective effect of HSP70 in an in vivo model of PD.
10.1073/pnas.140202897
20,783,160
The deposition of protein aggregates in neurons is a hallmark of neurodegenerative diseases caused by polyglutamine (polyQ) proteins. We analyzed the effects of the heat shock protein (Hsp) 70 chaperone system on the aggregation of fragments of huntingtin (htt) with expanded polyQ tracts. In vitro , Hsp70 and its cocha...
10.1038/nrn1587
The first report showing that the major effect of HSP70 and HSP40 on polyQ aggregation is to enhance polyQ solubility.
10.1126/science.1090389
60,377,485
Genome-wide screens were performed in yeast to identify genes that enhance the toxicity of a mutant huntingtin fragment or of α-synuclein. Of 4850 haploid mutants containing deletions of nonessential genes, 52 were identified that were sensitive to a mutant huntingtin fragment, 86 that were sensitive to α-synuclein, an...
10.1038/nrn1587
This genetic screen showed that the genes that enhance toxicity of the mutant huntingtin fragment in yeast cluster in the functionally related cellular processes of response to stress, protein folding and ubiquitin-dependent protein catabolism.
10.1146/annurev.neuro.25.032502.111311
38,270,278
▪ Abstract The overall organization of the peripheral autonomic nervous system has been known for many decades, but the mechanisms by which it is controlled by the central nervous system are just now coming to light. In particular, two major issues have seen considerable progress in the past decade. First, the pathways...
10.1038/nrn1902
Examines the control of BP in the more general context of the generation of autonomic patterns.
10.1161/hyp.38.4.896
101,981,182
In this study, we examine the role of NO located in the rostral ventrolateral medulla (RVLM) in the control of blood pressure and the activity of the sympathetic nervous system. To determine the effect of an increase in NO production in the RVLM on blood pressure in conscious rats, adenovirus vectors encoding either en...
10.1038/nrn1902
This important paper demonstrates that sustained changes in BP can be produced by altering the activity of relatively few neurons in the RVLM, which is strong evidence that the brain controls the 24-h average BP, presumably through the sympathetic nerves.
10.1161/hh1601.094988
18,473,055
In addition to the circulatory renin (REN)–angiotensin system (RAS), a tissue RAS having an important role in cardiovascular function also exists in the central nervous system. In the brain, angiotensinogen (AGT) is expressed in astrocytes and in some neurons important to cardiovascular control, but its functional role...
10.1038/nrn1902
Suggests that hypertension can be produced by upregulation of the renin–angiotensin system. This shows that the kidneys and vasculature cannot compensate for a brain defect and, therefore, that these organs cannot be the sole regulators of long-term BP, as is often stated.
10.1152/physrev.1997.77.1.75
125,314,645
The renal nerves are the communication link between the central nervous system and the kidney. In response to multiple peripheral and central inputs, efferent renal sympathetic nerve activity is altered so as to convey information to the major structural and functional components of the kidney, the vessels, glomeruli, ...
10.1038/nrn1902
Comprehensive, analytical review of the neural control of the kidney in health and disease, notably hypertension. The review argues strongly in favour of the role of renal sympathetic nerves in regulating the BP set-point.
10.1126/science.2063193
38,225,575
The arterial pressure of the adult human rarely deviates from normal by more than 10 to 15 percent during each day. To achieve such constancy, the body has a network of pressure control systems. Several are based on neural receptors that respond within seconds to help correct any abnormal pressure. The activities of th...
10.1038/nrn1902
Essential reading to understand how the kidneys contribute to the long-term regulation of BP by adjusting sodium excretion.
10.1126/science.270.5236.644
123,169,612
During stress, the activity of the sympathetic nervous system is changed in a global fashion, leading to an increase in cardiovascular function and a release of adrenal catecholamines. This response is thought to be regulated by a common set of brain neurons that provide a dual input to the sympathetic preganglionic ne...
10.1038/nrn1902
Illustrates the use of the pseudorabies virus in tracking the CNS networks that regulate the sympathetic nervous system. This particular paper argues that the RVLM contains neurons that innervate many types of sympathetic efferent, which is a conclusion that goes against a strict organotopic arrangement of RVLM barosen...
10.1523/jneurosci.04-02-00474.1984
10,258,271
We have studied the responses to electrical and chemical stimulation of the ventrolateral medulla in the chloralose-anesthetized, paralyzed, artificially ventilated rat. Locations of most active pressor responses were compared to regions containing neurons labeled immunocytochemically for phenylethanolamine N-methyltra...
10.1038/nrn1902
An influential paper that definitively established the pivotal role of the RVLM in controlling BP and gave strong support to the idea that the C1 cells are a crucial component of the network that regulates BP.
10.1111/j.1440-1681.2005.04206.x
100,727,282
SUMMARY 1. Increased dietary salt increases blood pressure in many hypertensive individuals, producing salt‐sensitive hypertension (SSH). The cause is unknown, but a major component appears to be activation of the sympathetic nervous system. The purpose of this short review is to present one hypothesis to explain how i...
10.1038/nrn1902
Interesting paper that describes potential CNS mechanisms of salt-dependent hypertension.
10.1111/j.1440-1681.2005.04209.x
20,273,929
SUMMARY 1. Humans experiencing intermittent hypoxia (IH) owing to recurrent apnoea syndromes exhibit serious cardiovascular morbidity, including high blood pressure, increased sympathetic nerve activity, cardiac arrhythmia and myocardial infarction. Although apnoeas are accompanied by a simultaneous decrease in arteria...
10.1038/nrn1902
The authors suggest that changes in the discharge characteristics of peripheral chemoreceptors at rest and in response to hypoxia could contribute to the development of hypertension associated with increased sympathetic tone caused by obstructive sleep apnoea.
10.1523/jneurosci.3115-05.2006
123,217,388
Sodium appetite can be enhanced by the adrenal steroid aldosterone via an unknown brain mechanism. A novel group of neurons in the nucleus tractus solitarius expresses the enzyme 11-β-hydroxysteroid dehydrogenase type 2, which makes them selectively responsive to aldosterone. Their activation parallels sodium appetite ...
10.1038/nrn1902
Provides the first definitive identification of brain neurons that are capable of detecting the circulating level of mineralocorticoid selectively. The study shows that the activity of these neurons correlates with sodium appetite.
10.1002/pmic.200900338
62,022,648
Abstract Although archaea, Gram‐negative bacteria, and mammalian cells constitutively secrete membrane vesicles (MVs) as a mechanism for cell‐free intercellular communication, this cellular process has been overlooked in Gram‐positive bacteria. Here, we found for the first time that Gram‐positive bacteria naturally pro...
10.1038/nrmicro3480
This article is the first extensive proteomic study of EVs produced by Gram-positive bacteria.
10.1073/pnas.1320118110
125,022,326
Significance Bacteria stimulate host cells in part via secreted products, some of which are packaged in membrane vesicles (MV). MV released by the major human pathogen Mycobacterium tuberculosis (Mtb) carry lipoprotein LpqH, a major agonist for host Toll-like receptor 2 (TLR2). This study identifies a gene, rv0431 , wh...
10.1038/nrmicro3480
This article describes the first gene shown to regulate vesiculogenesis in M. tuberculosis virR ); a mutant deficient in VirR overproduces EVs and is attenuated in virulence, suggesting that vesiculogenesis is important for Mycobacterium spp. pathogenesis.
10.1126/science.280.5369.1610
107,326,460
Glial cells produce myelin and contribute to axonal morphology in the nervous system. Two myelin membrane proteolipids, PLP and DM20, were shown to be essential for the integrity of myelinated axons. In the absence of PLP-DM20, mice assembled compact myelin sheaths but subsequently developed widespread axonal swellings...
10.1038/nrn2480
This landmark paper was the first in a series of studies in which knockouts of oligodendrocyte-expressed genes were used to demonstrate the important role of the oligodendrocyte in maintaining axon integrity.
10.1126/science.1103709
107,386,366
Olig1 and Olig2 are closely related basic helix-loop-helix (bHLH) transcription factors that are expressed in myelinating oligodendrocytes and their progenitor cells in the developing central nervous system (CNS). Olig2 is necessary for the specification of oligodendrocytes, but the biological functions of Olig1 during...
10.1038/nrn2480
This paper described a critical role for the oligodendrocyte-lineage-specific basic helix–loop–helix transcription factor OLIG1 in remyelination, and specifically in the differentiation process by which adult OPCs become remyelinating oligodendrocytes.
10.1083/jcb.118.4.889
79,388,989
We have shown previously that oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells isolated from adult rat optic nerves can be distinguished in vitro from their perinatal counterparts on the basis of their much slower rates of division, differentiation, and migration when grown in the presence of cortical astrocyte...
10.1038/nrn2480
This paper revealed how adult OPCs can change their properties, in response to environmental factors (growth factors) that are upregulated following CNS demyelination, in a manner conducive to their role in remyelination.
10.1523/jneurosci.2615-05.2006
104,411,954
Demyelination in the adult CNS can be followed by extensive repair. However, in multiple sclerosis, the differentiation of oligodendrocyte lineage cells present in demyelinated lesions is often inhibited by unknown factors. In this study, we test whether myelin debris, a feature of demyelinated lesions and an in vitro ...
10.1038/nrn2480
It is well established that CNS myelin contains proteins that are inhibitory to axon regeneration. This study revealed that CNS myelin is also inhibitory to remyelination, preventing OPCs from differentiating into remyelinating oligodendrocytes. The role of phagocytic macrophages in removing myelin debris following dem...
10.1523/jneurosci.18-02-00601.1998
103,546,337
In the past decade, considerable progress has been made in the understanding of the biology of rodent oligodendrocyte precursor cells and their role in the generation of oligodendrocytes in the developing and adult rodent CNS. Much less is known about human oligodendrocyte lineage cells and about the reasons for the fa...
10.1038/nrn2480
This study was the first to draw attention to the presence of oligodendrocyte-lineage cells in areas of chronic demyelination in MS, pointing to the failure of differentiation as a major explanation for the failure of remyelination (see also references147–149).
10.1126/science.285.5428.754
19,136,350
Self-renewing, totipotent embryonic stem (ES) cells may provide a virtually unlimited donor source for transplantation. A protocol that permits the in vitro generation of precursors for oligodendrocytes and astrocytes from ES cells was devised. Transplantation in a rat model of a human myelin disease shows that these E...
10.1038/nrn2480
This was the first study to demonstrate the use of ES cells in transplant-mediated myelination.
10.1073/pnas.0910651106
40,935,000
Anhedonia, the loss of pleasure or interest in previously rewarding stimuli, is a core feature of major depression. While theorists have argued that anhedonia reflects a reduced capacity to experience pleasure, evidence is mixed as to whether anhedonia is caused by a reduction in hedonic capacity. An alternative explan...
10.1038/nrn3027
This important study identifies the neurobiological underpinnings of a blunted response to positive stimuli, a key feature of depression.
10.1523/jneurosci.3874-05.2006
83,513,964
Small-world properties have been demonstrated for many complex networks. Here, we applied the discrete wavelet transform to functional magnetic resonance imaging (fMRI) time series, acquired from healthy volunteers in the resting state, to estimate frequency-dependent correlation matrices characterizing functional conn...
10.1038/nrn2575
This paper presented one of the first detailed analyses of small-world brain functional networks derived from human fMRI data.
10.1073/pnas.0606005103
104,236,048
Brain function depends on adaptive self-organization of large-scale neural assemblies, but little is known about quantitative network parameters governing these processes in humans. Here, we describe the topology and synchronizability of frequency-specific brain functional networks using wavelet decomposition of magnet...
10.1038/nrn2575
This study provides evidence for fractal or scale-invariant small-world networks across multiple frequency ranges and for their reconfiguration during cognitive tasks.
10.1126/science.286.5439.509
83,557,230
Systems as diverse as genetic networks or the World Wide Web are best described as networks with complex topology. A common property of many large networks is that the vertex connectivities follow a scale-free power-law distribution. This feature was found to be a consequence of two generic mechanisms: (i) networks exp...
10.1038/nrn2575
This landmark paper was the first to describe the scale-free organization of many complex networks and proposed a simple growth rule for their formation.
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/nrn2575
Using quantitative metabolic and haemodynamic measures, this paper first proposed the existence of an organized pattern of resting or default-mode brain activity.
10.1073/pnas.0701519104
125,322,518
Neuronal dynamics unfolding within the cerebral cortex exhibit complex spatial and temporal patterns even in the absence of external input. Here we use a computational approach in an attempt to relate these features of spontaneous cortical dynamics to the underlying anatomical connectivity. Simulating nonlinear neurona...
10.1038/nrn2575
This paper used a large-scale computational model to relate topological features of structural and functional brain networks at multiple timescales.
10.1152/jn.00950.2006
88,153,009
In temporal lobe epilepsy, changes in synaptic and intrinsic properties occur on a background of altered network architecture resulting from cell loss and axonal sprouting. Although modeling studies using idealized networks indicated the general importance of network topology in epilepsy, it is unknown whether structur...
10.1038/nrn2575
This paper used biologically realistic computational modelling to study the effects of epileptogenic cellular changes on the topology and dynamics of functional networks in the rat hippocampus.
10.1111/j.1471-4159.2012.07761.x
4,812,677
J. Neurochem. (2012) 122 , 208–220. Abstract The amyloid precursor protein (APP) is thought to be neuroprotective following traumatic brain injury (TBI), although definitive evidence at moderate to severe levels of injury is lacking. In the current study, we investigated histological and functional outcomes in APP−/− m...
10.1038/nrn.2017.29
This study demonstrates the in vivo importance of APPsα in neuroprotection in a model of acute brain lesioning.
10.1126/science.1083129
19,318,395
Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like ...
10.1038/nrn1727
Shows that mutations in dynein, which disrupt retrograde transport, lead to degeneration of projection neurons in mice.
10.1083/jcb.200201063
58,551,576
Acentral tenet of nerve growth factor (NGF) action that is poorly understood is its ability to mediate cytoplasmic signaling, through its receptor TrkA, that is initiated at the nerve terminal and conveyed to the soma. We identified an NGF-induced protein that we termed Pincher (pinocytic chaperone) that mediates endoc...
10.1038/nrn1727
This paper identifies a novel protein, Pincher, that promotes clathrin-independent macropinocytosis of NGF and TrkA.
10.1073/pnas.0408483102
62,063,089
The gliotransmitter d -serine is released upon (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate and metabotropic glutamate receptor stimulation, but the mechanisms involved are unknown. Here, by using a highly sensitive bioassay to continuously monitor extracellular d -serine levels, we have investigate...
10.1038/nrn2803
This study established the potential importance of exocytotic release of D -serine by astrocytes for regulating neuronal NMDA receptor activation.
10.1126/science.1144640
82,014,366
Astrocytes play active roles in brain physiology. They respond to neurotransmitters and modulate neuronal excitability and synaptic function. However, the influence of astrocytes on synaptic transmission and plasticity at the single synapse level is unknown. Ca 2+ elevation in astrocytes transiently increased the proba...
10.1038/nrn2803
The data presented suggest that vesicular glutamate release evoked by uncaging Ca 2+ in astrocytes promotes neuronal transmitter release by acting on presynaptic mGluRs.
10.1126/science.1116916
82,942,067
To investigate the role of astrocytes in regulating synaptic transmission, we generated inducible transgenic mice that express a dominant-negative SNARE domain selectively in astrocytes to block the release of transmitters from these glial cells. By releasing adenosine triphosphate, which accumulates as adenosine, astr...
10.1038/nrn2803
This paper shows that expression of a dominant negative SNARE in astrocytes, to suppress ATP release and downstream adenosine formation, leads to enhanced synaptic transmission.
10.1073/pnas.0506382102
62,580,860
Several lines of work have shown that astrocytes release glutamate in response to receptor activation, which results in a modulation of local synaptic activity. Astrocytic glutamate release is Ca 2+ -dependent and occurs in conjunction with exocytosis of glutamate containing vesicles. However, astrocytes contain a mill...
10.1038/nrn2803
This study shows that increases in astrocyte [Ca 2+ i lead to cell swelling and glutamate release through swelling-activated channels.
10.1073/pnas.0401960101
38,533,687
Calcium-binding synaptotagmins (Syts) are membrane proteins that are conserved from nematode to human. Fifteen Syts (Syts I–XV) have been identified in mammalian species. Syt I has been well studied and is a candidate for the Ca 2+ -sensor that triggers evoked exocytosis underlying fast synaptic transmission. Whereas t...
10.1038/nrn2803
An interesting analysis of a candidate Ca 2+ sensor for astrocyte exocytosis.
10.1073/pnas.0704935104
38,490,271
Optical imaging of individual vesicle exocytosis is providing new insights into the mechanism and regulation of secretion by cells. To study calcium-triggered secretion from astrocytes, we used acridine orange (AO) to label vesicles. Although AO is often used for imaging exocytosis, we found that imaging vesicles label...
10.1038/nrn2803
This study showed that astrocytes can exocytose ATP from lysosomes.
10.1073/pnas.071057198
101,088,460
The yeast cytosol contains multiple homologs of the DnaK and DnaJ chaperone family. Our current understanding of which homologs functionally interact is incomplete. Zuotin is a DnaJ homolog bound to the yeast ribosome. We have now identified the DnaK homolog Ssz1p/Pdr13p as zuotin's partner chaperone. Zuotin and Ssz1p ...
10.1038/nsmb.3435
The study revealed that the J-domain protein Zuo1 forms a stable complex with the Hsp70 Ssz1, termed ribosome-associated complex (RAC)
10.1073/pnas.062048399
61,248,178
Two proteins of the Hsp70 class (Ssb and Ssz1) and one of the J-type class (Zuo1) of molecular chaperones reside on the yeast ribosome, with Ssz1 forming a stable heterodimer with Zuo1. We designed experiments to address the roles of these two distantly related ribosome-associated Hsp70s and their functional relationsh...
10.1038/nsmb.3435
The work in refs. 10,11 revealed that Zuo1, Ssz1, and Ssb form a ribosome-bound chaperone triad
10.1073/pnas.0504400102
122,833,586
Soluble Hsp70 homologs cotranslationally interact with nascent polypeptides in all kingdoms of life. In addition, fungi possess a specialized Hsp70 system attached to ribosomes, which in Saccharomyces cerevisiae consists of the Hsp70 homologs Ssb1/2p, Ssz1p, and the Hsp40 homolog zuotin. Ssz1p and zuotin are assembled ...
10.1038/nsmb.3435
This work identified mammalian RAC consisting of the J-domain protein ZRF1/MPP1 and the Hsp70 Hsp70L1
10.1038/ncomms13563
114,258,385
Abstract Cotranslational chaperones assist in de novo folding of nascent polypeptides in all organisms. In yeast, the heterodimeric ribosome-associated complex (RAC) forms a unique chaperone triad with the Hsp70 homologue Ssb. We report the X-ray structure of full length Ssb in the ATP-bound open conformation at 2.6 Å ...
10.1038/nsmb.3435
This group solved the crystal structure of full-length ATP-bound Ssb and, together with work from ref. 55, identified Ssb's ribosome-binding domain
10.1083/jcb.200910074
4,684,339
The yeast Hsp70/40 system SSB–RAC (stress 70 B–ribosome-associated complex) binds to ribosomes and contacts nascent polypeptides to assist cotranslational folding. In this study, we demonstrate that nascent polypeptide–associated complex (NAC), another ribosome-tethered system, is functionally connected to SSB–RAC and ...
10.1038/nsmb.3435
In refs. 68 and 69, the authors demonstrated that RAC and Ssb serve a specific function in ribosome biogenesis
10.1073/pnas.1119184109
36,312,561
Zuo1 functions as a J-protein cochaperone of its partner Hsp70. In addition, the C terminus of Zuo1 and the N terminus of Ssz1, with which Zuo1 forms a heterodimer, can independently activate the Saccharomyces cerevisiae transcription factor pleiotropic drug resistance 1 (Pdr1). Here we report that activation of Pdr1 b...
10.1038/nsmb.3435
This work revealed that not only Ssz1 but also Zuo1 can activate the transcription factor Pdr1
10.1126/science.1109247
122,833,825
The existence of specialized molecular chaperones that interact directly with ribosomes is well established in microorganisms. Such proteins bind polypeptides exiting the ribosomal tunnel and provide a physical link between translation and protein folding. We report that ribosome-associated molecular chaperones have be...
10.1038/nsmb.3435
The studies in refs. 12 and 96 revealed that ZRF1/MPP11 interacts with ribosomes and is the human homolog of yeast Zuo1
10.1073/pnas.1007779107
107,289,047
The ability to control craving for substances that offer immediate rewards but whose long-term consumption may pose serious risks lies at the root of substance use disorders and is critical for mental and physical health. Despite its importance, the neural systems supporting this ability remain unclear. Here, we invest...
10.1038/nrn3119
Considering the long-term consequences of consuming cigarettes was associated with decreased craving and decreased activity in PFC regions associated with craving, and with increased activity in PFC regions associated with cognitive control. This study offers a specific cognitive–behavioural intervention to reduce cue-...
10.1073/pnas.1011455107
36,209,137
Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve ...
10.1038/nrn3119
Oral MPH decreased impulsivity in a drug-relevant emotional Stroop task, and this decrease was associated with normalization of activation in the rostroventral ACC (extending to the mOFC) and dACC in cocaine-addicted individuals. These results suggest that oral MPH may have therapeutic benefits in improving cognitive–b...
10.1002/ana.24513
101,644,666
Objective Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation of the X‐linked MECP2 gene and characterized by developmental regression during the first few years of life. The objective of this study was to investigate if the visual evoked potential (VEP) could be used as an unbiased, quantitative bi...
10.1038/nrneurol.2017.15
Compares the visual evoked responses in patients with Rett syndrome and with those in the Mecp2 mouse model of Rett syndrome.
10.1002/dneu.22452
83,124,364
ABSTRACT Oxytocin is a hypothalamic neuropeptide that has gained attention for the effects on social behavior. Recent findings shed new light on the mechanisms of oxytocin in synaptic plasticity and adaptively modifying neural circuits for social interactions such as conspecific recognition, pair bonding, and maternal ...
10.1038/nrneurol.2017.15
Demonstration of single-unit and population neuronal activity in response to auditory social stimuli, and responsiveness of this activity to behaviourally relevant pharmacological manipulation.
10.3928/01913913-20170320-04
29,178,415
Purpose: To evaluate the role of monocular video game play as an adjuvant to occlusion therapy in the treatment of anisometropic amblyopia. Methods: In a prospective randomized study design, 68 children with ages ranging from 6 to 14 years who had anisometropic amblyopia with a best corrected visual acuity (BCVA) in th...
10.1038/s41433-021-01669-w
This study has evaluated monocular video game therapy with conventional occlusion therapy
10.1186/1756-8935-1-9
103,931,373
Abstract The integrity of the genome is continuously challenged by both endogenous and exogenous DNA damaging agents. These damaging agents can induce a wide variety of lesions in the DNA, such as double strand breaks, single strand breaks, oxidative lesions and pyrimidine dimers. The cell has evolved intricate DNA dam...
10.1038/nrn4020
This review provides insight into how the chromatin remodelling response to DNA damage can assist in DNA repair.
10.1126/science.1243472
103,786,433
Not All Neurons Are Alike As life proceeds, many cells acquire individualized mutations. In the immune system, genome rearrangements generate useful antibody diversity. McConnell et al. (p. 632 ; see the Perspective by Macosko and McCarroll ) now show that human neurons also diversify. Neurons taken from postmortem hum...
10.1038/nrn4020
This study identifies the presence of aneuploidy and subchromosomal copy number variations in neurons obtained from human-induced pluripotent stem cell lines and postmortem human brains.
10.1073/pnas.231487398
83,022,592
A basic assumption about the normal nervous system is that its neurons possess identical genomes. Here we present direct evidence for genomic variability, manifested as chromosomal aneuploidy, among developing and mature neurons. Analysis of mouse embryonic cerebral cortical neuroblasts in situ detected lagging chromos...
10.1038/nrn4020
This study provides evidence that as many as one-third of the neuroblasts in the developing brain are aneuploid and, together with references 28–36, it also provides evidence that aneuploid postmitotic neurons are a part of the normal mature brain.
10.1146/annurev.neuro.24.1.167
83,551,177
▪ Abstract The prefrontal cortex has long been suspected to play an important role in cognitive control, in the ability to orchestrate thought and action in accordance with internal goals. Its neural basis, however, has remained a mystery. Here, we propose that cognitive control stems from the active maintenance of pat...
10.1038/nrn2667
This authoritative review provides a fundamental background on the cognitive control function of the PFC. It focuses on the theory that action goals are maintained as distributed patterns of activity in PFC, as a consequence of which other neural systems are biased to perform in goal-relevant ways.
10.1126/science.1088545
62,167,115
The prefrontal cortex (PFC) subserves cognitive control: the ability to coordinate thoughts or actions in relation with internal goals. Its functional architecture, however, remains poorly understood. Using brain imaging in humans, we showed that the lateral PFC is organized as a cascade of executive processes from pre...
10.1038/nrn2667
This paper reports the first neuroimaging experiment showing a rostro-caudal gradient of activity in frontal cortex based on a systematic manipulation of abstraction across conditions.
10.1162/jocn.2009.21132
38,742,793
Past experience is hypothesized to reduce computational demands in PFC by providing bottom–up predictive information that informs subsequent stimulus-action mapping. The present fMRI study measured cortical activity reductions (“neural priming”/“repetition suppression”) during repeated stimulus classification to invest...
10.1038/nrn2667
This fMRI study of repetition priming provides within-subject evidence for a rostro-caudal functional gradient along the ventrolateral PFC.
10.1002/cne.902860306
18,958,308
Abstract An investigation of the architectonic organization and intrinsic connections of the prefrontal cortex was conducted in rhesus monkeys. Cytoarchitectonic analysis indicates that in the prefrontal cortex there are two trends of gradual change in laminar characteristics that can be traced from limbic periallocort...
10.1038/nrn2667
In this study, anatomists Barbas and Pandya present data from rhesus monkeys demonstrating that there is a gradient of laminar organization within the frontal cortex from the most anterior (least differentiated) to posterior portions.
10.1523/jneurosci.2419-07.2007
62,587,866
The different prefrontal cortical regions exert executive control over processing occurring in posterior cortical regions. We examined with the autoradiographic method, in the macaque monkey, the course and terminations of the efferent corticocortical connections of the rostral prefrontal region, the function of which ...
10.1038/nrn2667
Using the autoradiographic method, this study reports the course and terminations of the efferent cortico–cortical connections of the rostral prefrontal region (area 10) in macaque monkeys.
10.1152/jn.90355.2008
125,210,087
Two functionally distinct, and potentially competing, brain networks have been recently identified that can be broadly distinguished by their contrasting roles in attention to the external world versus internally directed mentation involving long-term memory. At the core of these two networks are the dorsal attention s...
10.1038/nrn2667
This study applied functional connectivity analysis to resting state fMRI data and characterized a specific fronto-parietal network that was coherent with the frontal pole (approximately area 10). In the frontal cortex, this analysis identified a dorsal rostro-caudal network that closely corresponds to the gradient of ...
10.1038/ncomms8169
20,630,081
Abstract Aggregate signals in cortex are known to be spatiotemporally organized as propagating waves across the cortical surface, but it remains unclear whether the same is true for spiking activity in individual neurons. Furthermore, the functional interactions between cortical neurons are well documented but their sp...
10.1038/nrn.2018.20
This paper specifically demonstrates that travelling waves modulate spiking activity in the motor cortex during normal waking behaviour.
10.1073/pnas.88.24.11037
122,221,555
This paper introduces the use of magnetic field tomography (MFT), a noninvasive technique based on distributed source analysis of magnetoencephalography data, which makes possible the three-dimensional reconstruction of dynamic brain activity in humans. MFT has a temporal resolution better than 1 msec and a spatial acc...
10.1038/nrn.2018.20
With a novel technique for analysing data from magnetoencephalography, this study reports a unique, global anterior-to-posterior phase shift in gamma oscillations in the human cortex.
10.1126/science.283.5402.695
44,983,463
The receptive field of a visual neuron is classically defined as the region of space (or retina) where a visual stimulus evokes a change in its firing activity. At the cortical level, a challenging issue concerns the roles of feedforward, local recurrent, intracortical, and cortico-cortical feedback connectivity in rec...
10.1038/nrn.2018.20
This study provided experimental evidence for evoked travelling waves in the mammalian cortex and uses intracellular recordings in which subthreshold depolarizing responses outside the spiking receptive field become more delayed for stimuli presented farther from the receptive field centre.
10.1126/science.282.5389.746
102,608,085
A fundamental question in cognitive science is whether animals can represent numerosity (a property of a stimulus that is defined by the number of discriminable elements it contains) and use numerical representations computationally. Here, it was shown that rhesus monkeys represent the numerosity of visual stimuli and ...
10.1038/nrn1626
A pioneering behavioural study showing that monkeys are able to understand the ordinal relationship of numerosities.
10.1126/science.1102085
103,693,160
Is calculation possible without language? Or is the human ability for arithmetic dependent on the language faculty? To clarify the relation between language and arithmetic, we studied numerical cognition in speakers of Mundurukú, an Amazonian language with a very small lexicon of number words. Although the Mundurukú ...
10.1038/nrn1626
Humans that lack number words for larger numerosities perform approximate numerical computations.
10.1126/science.1094492
19,185,636
Members of the Pirahã tribe use a “one-two-many” system of counting. I ask whether speakers of this innumerate language can appreciate larger numerosities without the benefit of words to encode them. This addresses the classic Whorfian question about whether language can determine thought. Results of numerical tasks w...
10.1038/nrn1626
Cardinality judgments in humans without a verbal number concept are astonishingly poor and reminiscent of the discrimination performances of animals.
10.1126/science.1072493
83,022,761
Deriving the quantity of items is an abstract form of categorization. To explore it, monkeys were trained to judge whether successive visual displays contained the same quantity of items. Many neurons in the lateral prefrontal cortex were tuned for quantity irrespective of the exact physical appearance of the displays....
10.1038/nrn1626
The authors taught monkeys to judge whether two successively presented visual displays contained the same number of items. Neurons in the prefrontal cortex were maximally activated by a specific number of items, but were unaffected by changes in the exact appearance of the stimuli.
10.1073/pnas.0402239101
20,807,643
Recent electrophysiological studies in monkeys have implicated the prefrontal cortex (PFC) and posterior parietal cortex (PPC) in numerical judgments. The functional organization and respective contributions of these (and other) cortical areas, however, are unknown; their neural activity during numerical judgments has ...
10.1038/nrn1626
A comparison of numerosity-selective neurons recorded in three areas (prefrontal, posterior parietal and anterior temporal) of the same monkeys. Quantity information was first represented in the posterior parietal cortex, but the prefrontal cortex showed the highest proportion of numerosity-selective neurons.
10.1152/jn.00694.2003
40,227,883
Generation of information about the temporal order of events is essential for the control of memory-based behavioral tasks. We studied cellular activity in the lateral prefrontal cortex (LPFC) in two monkeys that were required to remember the temporal order in which visual objects were presented. In this report, we foc...
10.1038/nrn1626
Single-cell study showing that neurons in the prefrontal cortex of macaques encode the numerical rank of successively-displayed objects.
10.1073/pnas.1010529108
125,332,481
Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxi...
10.1038/nrn3071
The first demonstration of an important role of intestinal microbiota early in life in brain development and adult anxiety-like behaviour.
10.1152/ajpendo.90796.2008
58,402,967
The vagal afferent pathway is important in short-term regulation of food intake, and decreased activation of this neural pathway with long-term ingestion of a high-fat diet may contribute to hyperphagic weight gain. We tested the hypothesis that expression of genes encoding receptors for orexigenic factors in vagal aff...
10.1038/nrn3071
An interesting study that demonstrates the molecular mechanisms underlying fat induced phenotypic changes in vagal afferents, which may play a part in the decreased influences of interoceptive mechanisms in diet-induced obesity.
10.1073/pnas.0506806103
123,188,827
We pursue the hypothesis that neuronal placement in animals minimizes wiring costs for given functional constraints, as specified by synaptic connectivity. Using a newly compiled version of the Caenorhabditis elegans wiring diagram, we solve for the optimal layout of 279 nonpharyngeal neurons. In the optimal layout, mo...
10.1038/nrn3214
This study shows that the anatomical layout (component placement) of the neurons comprising the C. elegans nervous system is near-minimal given network functionality.
10.1126/science.1089662
83,375,608
Brains perform with remarkable efficiency, are capable of prodigious computation, and are marvels of communication. We are beginning to understand some of the geometric, biophysical, and energy constraints that have governed the evolution of cortical networks. To operate efficiently within these constraints, nature has...
10.1038/nrn3214
This is a seminal review of cost constraints on the efficiency of nervous systems and their adaptability.
10.1186/1744-8069-3-9
19,636,962
Long-term potentiation (LTP) at synapses of nociceptive nerve fibres is a proposed cellular mechanism underlying some forms of hyperalgesia. In this review fundamental properties of LTP in nociceptive pathways are described. The following topics are specifically addressed: A concise definition of LTP is given and a dif...
10.1038/nrn.2016.68
A comprehensive review of LTP in spinal pain pathways and its contribution to chronic pain.
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/nrn.2016.68
This report shows that activity in the ACC in humans can be triggered by social exclusion.
10.1126/science.1191792
39,238,964
Pain in the Brain One of the major challenges in pain research is finding ways to reverse chronic pain. Synaptic long-term potentiation (LTP) at spinal or cortical levels is a cellular model of chronic pain. X.-Y. Li. et al. (p. 1400 ) studied the role of the enzyme protein kinase M zeta (PKMζ) in neurons of the anteri...
10.1038/nrn.2016.68
This paper demonstrates that NMDAR-mediated LTP of AMPAR function in the ACC contributes to behavioural sensitization in an animal model of neuropathic pain.
10.1126/science.1094804
83,027,763
Although the molecular, cellular, and systems mechanisms required for initial memory processing have been intensively investigated, those underlying permanent memory storage remain elusive. We present neuroanatomical, pharmacological, and genetic results demonstrating that the anterior cingulate cortex plays a critical...
10.1038/nrn.2016.68
This study identifies an important role for the ACC in remote fear memory.
10.1105/tpc.109.069666
83,228,736
Abstract Knowledge remains limited about how fungal pathogens that colonize living plant cells translocate effector proteins inside host cells to regulate cellular processes and neutralize defense responses. To cause the globally important rice blast disease, specialized invasive hyphae (IH) invade successive living ri...
10.1038/nrmicro3119
This study characterizes the BIC and provides live-cell imaging of fungus secreting fluorescently labeled effectors during rice cell invasion. A sensitive nuclear targeting assay is described for analyses of effector translocation and cell-to-cell movement.
10.1073/pnas.1112708109
40,672,425
In response to pathogen attack, plant cells secrete antimicrobial molecules at the site of infection. However, how plant pathogens interfere with defense-related focal secretion remains poorly known. Here we show that the host-translocated RXLR-type effector protein AVRblb2 of the Irish potato famine pathogen Phytophth...
10.1038/nrmicro3119
This paper characterizes Avrblb2, which is an RXLR-type effector protein of P. infestans . The results suggest that Avrblb2 targets PLCP C14 and prevents its secretion into the apoplast.
10.1111/j.1365-2958.2011.07728.x
26,837,686
Summary Ustilago maydis is a biotrophic fungal pathogen that colonizes living tissue of its host plant maize. Based on transcriptional upregulation during biotrophic development we identified the pit ( p roteins i mportant for t umours) cluster, a novel gene cluster comprising four genes of which two are predicted to e...
10.1038/nrmicro3119
The authors describe a novel U. maydis gene cluster that contains two adjacent and divergently arranged genes which encode the fungal membrane protein Pit1 and the apoplastic effector Pit2.
10.1073/pnas.0914408107
41,149,390
Fungal and oomycete plant pathogens translocate effector proteins into host cells to establish infection. However, virulence targets and modes of action of their effectors are unknown. Effector AVR3a from potato blight pathogen Phytophthora infestans is translocated into host cells and occurs in two forms: AVR3a KI , w...
10.1038/nrmicro3119
This study provides genetic evidence that the translocated oomycete AVR effector AVR3a is an essential virulence factor that targets and stabilizes the plant E3 ligase CMPG1, potentially to prevent host cell death during the biotrophic phase of infection.
10.1111/tpj.12237
124,736,212
Summary It has been reported that filament‐forming surface proteins such as hydrophobins are important virulence determinants in fungi and are secreted during pathogenesis. Such proteins have not yet been identified in obligate biotrophic pathogens such as rust fungi. Rust transferred protein 1 ( RTP 1p), a rust protei...
10.1038/nrmicro3119
The authors propose a structural function for the rust effector Rtp1. This protein forms amyloid-like filaments in vitro , and localizes to protuberances of the extrahaustorial matrix that reach into the host cytoplasm.
10.1105/tpc.109.072983
109,045,605
Abstract Translocation of pathogen effector proteins into the host cell cytoplasm is a key determinant for the pathogenicity of many bacterial and oomycete plant pathogens. A number of secreted fungal avirulence (Avr) proteins are also inferred to be delivered into host cells, based on their intracellular recognition b...
10.1038/nrmicro3119
The authors show by immunolocalization that the flax rust AVR effector AvrM is translocated into flax cells during infection. They present evidence that AvrM and AvrL567 can enter plant cells in the absence of the pathogen.
10.1146/annurev.micro.62.081307.162903
103,086,767
The fundamental details of how nutritional stress leads to elevating (p)ppGpp are questionable. By common usage, the meaning of the stringent response has evolved from the specific response to (p)ppGpp provoked by amino acid starvation to all responses caused by elevating (p)ppGpp by any means. Different responses have...
10.1038/nrmicro3448
A review that summarizes compelling evidence for the role of (p)ppGpp in growth rate control in E. coli
10.1038/embor.2012.106
39,710,629
During the stringent response, Escherichia coli enzyme RelA produces the ppGpp alarmone, which in turn regulates transcription, translation and replication. We show that ppGpp dramatically increases the turnover rate of its own ribosome‐dependent synthesis by RelA, resulting in direct positive regulation of an enzyme b...
10.1038/nrmicro3448
A study showing that ppGpp markedly increases the rate of its own synthesis by RelA through a positive allosteric feedback mechanism that had not been described previously for any enzyme.
10.1073/pnas.70.5.1564
17,576,755
The nucleotides ppGpp and pppGpp accumulate when wild-type, but not rel - , strains of Escherichia coli are starved for required amino acids. These compounds are synthesized on ribosomes, in the presence of the product of the rel gene, from GDP and GTP; ATP is used as the phosphate donor. The signal for making these co...
10.1038/nrmicro3448
Biochemical investigations demonstrating tRNA- and ribosome-dependent activation of RelA-mediated (p)ppGpp synthesis.
10.1073/pnas.1102255108
19,714,080
The RelA-mediated stringent response is at the heart of bacterial adaptation to starvation and stress, playing a major role in the bacterial cell cycle and virulence. RelA integrates several environmental cues and synthesizes the alarmone ppGpp, which globally reprograms transcription, translation, and replication. We ...
10.1038/nrmicro3448
An in vivo single-molecule tracking analysis of RelA, the results of which suggest that ppGpp is synthesized by RelA when it is off, rather than on, the ribosome.
10.1038/embor.2013.106
16,860,427
The bacterial stringent response links nutrient starvation with the transcriptional control of genes. This process is initiated by the stringent factor RelA, which senses the presence of deacylated tRNA in the ribosome as a symptom of amino‐acid starvation to synthesize the alarmone (p)ppGpp. Here we report a cryo‐EM s...
10.1038/nrmicro3448
A cryo-EM analysis of RelA in complex with the ribosome.
10.1111/j.1365-2958.2006.05442.x
45,319,844
Summary Bacteria respond to nutritional stresses by producing an intracellular alarmone, guanosine 5′‐(tri)diphosphate, 3′‐diphosphate [(p)ppGpp], which triggers the stringent response resulting in growth arrest and expression of resistance genes. In Escherichia coli , upon fatty acid or carbon starvation, SpoT enzyme ...
10.1038/nrmicro3448
A paper describing the molecular mechanism of SpoT regulation by ACP.
10.1126/science.1211037
125,092,705
During growth arrest, bacteria tolerate the presence of antibiotics, thanks to mechanisms that protect against oxidant stress.
10.1038/nrmicro3448
A study demonstrating that the stringent response induces antibiotic tolerance by eliciting a specific cell survival programme rather than by slowing down bacterial growth.
10.1111/j.1365-2958.2007.06018.x
82,539,709
Summary Bacterial alarmone (p)ppGpp, is a global regulator responsible for the stringent control. Two homologous (p)ppGpp synthetases, RelA and SpoT, have been identified and characterized in Escherichia coli , whereas Gram‐positive bacteria such as Bacillus subtilis have been thought to possess only a single RelA‐SpoT...
10.1038/nrmicro3448
One of the first reports to identify a single-domain small alarmone synthetase enzyme.