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10.1126/science.1152506
80,713,057
The mammalian circadian clockwork is modeled as transcriptional and posttranslational feedback loops, whereby circadian genes are periodically suppressed by their protein products. We show that adenosine 3′,5′-monophosphate (cAMP) signaling constitutes an additional, bona fide component of the oscillatory network. cAMP...
10.1038/nrn3086
An important study that explores the role of cAMP signalling in the SCN. Among other findings, the authors show that the transcriptional activity of the CRE is strongly rhythmic in the SCN. Importantly, pharmacological blockade of adenylyl cyclase activity reduced cAMP levels, suppressed CRE expression and greatly redu...
10.1126/science.288.5472.1796
103,279,231
Experiments with vesicles containing N -methyl- d -aspartate (NMDA) receptor 2B (NR2B subunit) show that they are transported along microtubules by KIF17, a neuron-specific molecular motor in neuronal dendrites. Selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of mLin-10 (Mi...
10.1038/nrn2153
Identified KIF17, a member of the kinesin family, as a motor involved in the transport of vesicles carrying newly synthesized NMDARs along microtubules.
10.1073/pnas.96.26.15262
38,715,801
N -methyl- d -aspartate receptors (NMDARs) are Ca 2+ -permeable glutamate-gated ion channels whose physiological properties in neurons are modulated by protein kinase C (PKC). The present study was undertaken to determine the role in PKC-induced potentiation of the NR1 and NR2A C-terminal tails, which serve as targets ...
10.1038/nrn2153
The first evidence that NMDARs comprising mutant NR1 and NR2A subunits lacking all known sites of PKC phosphorylation exhibit PKC potentiation.
10.1097/j.pain.0000000000000707
103,642,442
Abstract Patients with fibromyalgia (FM) show characteristically enhanced unpleasantness to painful and nonpainful sensations accompanied by altered neural responses. The diagnostic potential of such neural alterations, including their sensitivity and specificity to FM (vs healthy controls) is unknown. We identify a br...
10.1038/nrneurol.2017.122
This study shows decoding of a chronic pain condition from brain activity.
10.1038/srep34853
82,966,296
Abstract Chronic pain remains poorly understood; yet it is associated with the reorganization of the nervous system. Here, we demonstrate that a unitary global measure of functional connectivity, defined as the extent of degree rank order disruption, k D , identifies the chronic pain state. In contrast, local degree di...
10.1038/nrneurol.2017.122
This study uses graph theory to demonstrate that chronic pain is associated with a global change in brain connectivity.
10.1073/pnas.0503654102
38,449,807
Bacterial evolution toward endosymbiosis with eukaryotic cells is associated with extensive bacterial genome reduction and loss of metabolic and regulatory capabilities. Here we examined the rate and process of genome reduction in the bacterium Salmonella enterica by a serial passage experimental evolution procedure. T...
10.1038/nrmicro2670
Experimental support for the hypothesis that bacteria which are subject to frequent population bottlenecks can rapidly delete large amounts of DNA from their genomes.
10.1126/science.1134196
83,481,272
Previous studies have suggested that the minimal cellular genome could be as small as 400 kilobases. Here, we report the complete genome sequence of the psyllid symbiont Carsonella ruddii, which consists of a circular chromosome of 159,662 base pairs, averaging 16.5% GC content. It is by far the smallest and most AT-ri...
10.1038/nrmicro2670
A report of the first discovery of a tiny cellular genome that is only about one-third the size of the smallest previously reported bacterial genome but retains some genes that are devoted to nutrition of the host insect.
10.1073/pnas.0804445105
16,807,642
A fundamental biological question is what forces shape the guanine plus cytosine (GC) content of genomes. We studied the specificity and rate of different mutational biases in real time in the bacterium Salmonella typhimurium under conditions of strongly reduced selection and in the absence of the major DNA repair syst...
10.1038/nrmicro2670
Experimental support for the role of DNA repair enzymes and small effective population sizes in the decreased GC content seen in most endosymbiont genomes.
10.1073/pnas.1013465108
103,798,183
The evolution of intimate symbiosis requires the coordination of gene expression and content between the distinct partner genomes; this coordination allows the fusion of capabilities of each organism into a single integrated metabolism. In aphids, the 10 essential amino acids are scarce in the phloem sap diet and are s...
10.1038/nrmicro2670
Work showing a high level of coordination between gene expression in the aphid host and the B. aphidicola symbiont, and highlighting the types of host co-adaptations that allow genome reduction in mutualistic endosymbionts.
10.1073/pnas.1003379107
18,956,502
As an obligatory parasite of humans, the body louse ( Pediculus humanus humanus ) is an important vector for human diseases, including epidemic typhus, relapsing fever, and trench fever. Here, we present genome sequences of the body louse and its primary bacterial endosymbiont Candidatus Riesia pediculicola. The body l...
10.1038/nrmicro2670
The complete louse and endosymbiont genomes reveal that no bacterial genes have been transferred to the insect genome and that genome reduction in ' Ca. Riesia pediculicola' has not been associated with gene transfer to the host, as is common in organelles.
10.1242/dev.120.4.911
104,229,110
In this study we have cloned the chick Hoxa-2 gene and analysed its expression during early development. We find that Hoxa-2 has a rostral limit of expression in the rhombencephalic neural tube corresponding precisely to the boundary between rhombomeres (r)1 and 2; a limit further rostral than any other Hox gene report...
10.1038/nrn1221
This important paper describes the analysis of chick Hoxa2 expression. Through grafting experiments, evidence is provided that the expression of Hoxa2 is intrinsic to the premigratory NCC population, thereby supporting a NCC prepatterning model.
10.1242/dev.122.10.3229
83,558,828
To investigate the influence of hindbrain segmentation on craniofacial patterning we have studied the long term fate of neural crest (NC) subpopulations of individual rhombomeres (r), using quail-chick chimeras. Mapping of all skeletal and muscle connective tissues developing from these small regions revealed several n...
10.1038/nrn1221
A landmark study in avian embryos, showing detailed fate-mapping data of rhombomeric NCCs and their contribution to the craniofacial structures.
10.1126/science.1075703
41,641,795
The success of vertebrates was due in part to the acquisition and modification of jaws. Jaws are principally derived from the branchial arches, embryonic structures that exhibit proximodistal polarity. To investigate the mechanisms that specify the identity of skeletal elements within the arches, we examined mice lacki...
10.1038/nrn1221
References 65 and 66 are key papers demonstrating the dorsoventral patterning role of Dlx genes. A double Dlx-5/-6 knockout in the mouse resulted in the homeotic transformation of the lower jaw into a mirror image of the upper jaw.
10.1126/science.1064540
125,247,532
Cranial neural crest cells generate the distinctive bone and connective tissues in the vertebrate head. Classical models of craniofacial development argue that the neural crest is prepatterned or preprogrammed to make specific head structures before its migration from the neural tube. In contrast, recent studies in sev...
10.1038/nrn1221
A key study revisiting Noden's transplantation experiments and showing that duplication of the first arch skeleton could be obtained only when the FGF8-expressing isthmic organizer was included in the graft of presumptive first arch NCCs. It supports plasticity of cranial NCCs and patterning by environmental signals.
10.1242/dev.129.4.1061
125,284,865
The vertebrate face contains bones that differentiate from mesenchymal cells of neural crest origin, which colonize the median nasofrontal bud and the first branchial arches. The patterning of individual facial bones and their relative positions occurs through mechanisms that remained elusive. During the early stages o...
10.1038/nrn1221
This landmark work demonstrated the role of the foregut endoderm in the control of cranial NCC development. The endoderm was shown to be a source of positional and morphogenetic information to pattern the face and jaw skeleton. It supports a NCC plasticity model.
10.1242/dev.129.18.4301
62,636,342
Diencephalic, mesencephalic and metencephalic neural crest cells are skeletogenic and derive from neural folds that do not express Hox genes. In order to examine the influence of Hox gene expression on skull morphogenesis, expression of Hoxa2, Hoxa3 and Hoxb4 in conjunction with that of the green fluorescent protein ha...
10.1038/nrn1221
References 74 and 80 revealed that Hox-expressing cranial NCCs in the first arch environment are unable to yield a jaw skeleton, thereby raising important evolutionary issues. Moreover, they indicate that Hox expression negatively regulates neural crest-mediated skeletogenesis.
10.1242/dev.00673
102,400,845
During development neural crest cells give rise to a wide variety of specialized cell types in response to cytokines from surrounding tissues. Depending on the cranial-caudal level of their origin, different populations of neural crest cells exhibit differential competence to respond to these signals as exemplified by ...
10.1038/nrn1221
An interesting analysis of cultured NCCs that investigates the differential skeletogenic potential of cranial versus trunk NCCs. It is shown that the same signal (for example, FGF) can induce dissimilar cell fate decisions in the two populations in vitro . These differences correlate, at least in part, with their Hox g...
10.1242/dev.00554
124,305,016
Hox genes are known key regulators of embryonic segmental identity, but little is known about the mechanisms of their action. To address this issue,we have analyzed how Hoxa2 specifies segmental identity in the second branchial arch. Using a subtraction approach, we found that Ptx1 was upregulated in the second arch me...
10.1038/nrn1221
A paper that reports important observations about Hoxa2 -dependent molecular mechanisms in second pharyngeal arch patterning. It implicates Hoxa2 in a pathway that antagonizes epithelial FGF signalling.
10.1242/dev.00397
104,361,005
A fundamental set of patterning genes may define the global organization of the craniofacial region. One of our goals has been to identify these basic patterning genes and understand how they regulate outgrowth of the frontonasal process, which gives rise to the mid and upper face. We identified a molecular boundary in...
10.1038/nrn1221
In this key paper, a region of the frontonasal ectoderm that expresses Fgf8 and Shh is identified as an organizing centre, which promotes morphogenesis and outgrowth of the frontonasal NCC mesenchyme. It supports a NCC plasticity model.
10.1126/science.1077827
40,058,113
Cellular and molecular mechanisms underlying differences in beak morphology likely involve interactions among multiple embryonic populations. We exchanged neural crest cells destined to participate in beak morphogenesis between two anatomically distinct species. Quail neural crest cells produced quail beaks in duck hos...
10.1038/nrn1221
An important study showing that the ability to generate beak morphology is an intrinsic property of NCCs. By grafting presumptive cranial NCCs between duck and quail, it was shown that NCCs carry out their own species-specific morphogenetic programme. It supports a NCC prepatterning model.
10.1242/dev.00339
20,352,808
A conserved endothelin 1 signaling pathway patterns the jaw and other pharyngeal skeletal elements in mice, chicks and zebrafish. In zebrafish,endothelin 1 (edn1 or sucker) is required for formation of ventral cartilages and joints in the anterior pharyngeal arches of young larvae. Here we present genetic analyses in t...
10.1038/nrn1221
The elegant analyses in zebrafish that are described in references 102 and 103 are interesting examples of the morphogenetic activity of locally secreted factors in branchial arch development. A functional gradient of the epithelial signalling factor endothelin-1 provides positional information to NCCs for the correct ...
10.1101/gad.931701
38,571,595
Neural crest cells play a key role in craniofacial development. The endothelin family of secreted polypeptides regulates development of several neural crest sublineages, including the branchial arch neural crest. The basic helix–loop–helix transcription factor dHAND is also required for craniofacial development, and in...
10.1038/nrn1221
References 110 and 112 are two important studies that dissected the molecular pathway downstream of endothelin-1, which is involved in ventral patterning of the first pharyngeal arch. Dlx6 directly regulates the expression of dHAND in response to endothelin-1 signalling from the arch epithelium.
10.1126/science.1068310
103,518,153
Genes involved in late specification of the mandibular arch, the source of the vertebrate jaw, are expressed with similar patterns in the oral regions of chick and lamprey embryos. However, morphological comparisons indicate that apparently orthologous homeobox genes were expressed in different subdivisions of the ecto...
10.1038/nrn1221
This important paper offers a comparison of the distribution and function of signalling molecules and downstream homeobox genes in the oral regions of jawed (chick) and jawless (lamprey) vertebrate embryos. It raises interesting issues about the evolution of the mandibular arch in the vertebrate lineage.
10.1101/gad.250703
41,493,399
Development of the pharyngeal region depends on the interaction and integration of different cell populations, including surface ectoderm, foregut endoderm, paraxial mesoderm, and neural crest. Mice homozygous for a hypomorphic allele of Fgfr1 have craniofacial defects, some of which appeared to result from a failure i...
10.1038/nrn1221
This interesting paper shows that functional inactivation of Fgfr1 in the mouse results in patterning defects of the second pharyngeal arch. The data indicate that Fgfr1 function is required to create a permissive environment for NCC migration.
10.1073/pnas.0510188103
81,542,661
Much evidence from studies in humans and animals supports the hypothesis that alcohol addiction is a complex disease with both hereditary and environmental influences. Molecular determinants of excessive alcohol consumption are difficult to study in humans. However, several rodent models show a high or low degree of al...
10.1038/nrn.2016.85
This large-scale microarray study used mice that were selectively bred to consume large amounts of alcohol and inbred mouse lines that prefer or avoid alcohol. The authors found that the transcripts of genes in specific signalling cascades, including the HRAS–MKK1–ERK1/2 axis, are enriched in the brains of mice that co...
10.1073/pnas.1211844110
29,341,810
The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing ...
10.1038/nrn.2016.85
The authors identified a role for the small G protein RAS-GRF2 in alcohol consumption in mice. The authors further provided a link between RAS-GRF2–ERK1/2 signalling and dopamine release. Human studies identified a SNP within the RGS2 gene as a risk factor for alcohol drinking during adolescence.
10.1162/jocn.1997.9.4.534
62,218,824
Recall of paired-associate lists (declarative memory) and mirror-tracing skills (procedural memory) was assessed after retention intervals defined over early and late nocturnal sleep. In addition, effects of sleep on recall were compared with those of early and late retention intervals filled with wakefulness. Twenty h...
10.1038/nrn2762
The first paper to show that SWS preferentially consolidates declarative memories, whereas REM sleep primarily supports procedural memories.
10.1126/science.1138581
62,218,825
Sleep facilitates memory consolidation. A widely held model assumes that this is because newly encoded memories undergo covert reactivation during sleep. We cued new memories in humans during sleep by presenting an odor that had been presented as context during prior learning, and so showed that reactivation indeed cau...
10.1038/nrn2762
Odours associated with the encoding of visuo-spatial memories were used as cues during post-learning SWS to re-activate the memories. The memory enhancement produced by this re-activation compellingly demonstrates a causal role of re-activations for sleep-dependent consolidation.
10.1126/science.8036517
20,689,647
Simultaneous recordings were made from large ensembles of hippocampal "place cells" in three rats during spatial behavioral tasks and in slow-wave sleep preceding and following these behaviors. Cells that fired together when the animal occupied particular locations in the environment exhibited an increased tendency to ...
10.1038/nrn2762
A pioneering study revealing that in rats spatial–temporal patterns of neuronal firing in the hippocampus during learning are re-activated in the same order during subsequent SWS.
10.1073/pnas.0705454104
3,552,533
After encoding, memory traces are initially fragile and have to be reinforced to become permanent. The initial steps of this process occur at a cellular level within minutes or hours. Besides this rapid synaptic consolidation, systems consolidation occurs within a time frame of days to years. For declarative memory, th...
10.1038/nrn2762
Using functional brain imaging the authors show that sleep leads to a redistribution of memory traces from the hippocampus to neocortical sites for long-term storage.
10.1073/pnas.0437938100
123,945,471
Both neocortical and hippocampal networks organize the firing patterns of their neurons by prominent oscillations during sleep, but the functional role of these rhythms is not well understood. Here, we show a robust correlation of neuronal discharges between the somatosensory cortex and hippocampus on both slow and fin...
10.1038/nrn2762
First study in rats and mice that demonstrated a temporally fine-tuned relationship between slow oscillations, spindles and sharp-wave ripples possibly underlying the transfer of information between the hippocampus and neocortical regions.
10.1126/science.1085952
83,499,335
In March 2003, a novel coronavirus (SARS-CoV) was discovered in association with cases of severe acute respiratorysyndrome (SARS). The sequence of the complete genome of SARS-CoV was determined, and the initial characterization of the viral genome is presented in this report. The genome of SARS-CoV is 29,727 nucleotide...
10.1038/nrmicro775
References 17 and 18 are the first reports of the complete genome sequences of two SARS-CoV isolates (TOR2 and Urbani strains, respectively). In each case, the authors present the viral genome organization, describe the main features of the predicted ORFs and provide a phylogenetic analysis that places SARS-CoV in a ne...
10.1126/science.1085658
104,301,629
A novel coronavirus has been identified as the causative agent of severe acute respiratory syndrome (SARS). The viral main proteinase (M pro , also called 3CL pro ), which controls the activities of the coronavirus replication complex, is an attractive target for therapy. We determined crystal structures for human coro...
10.1038/nrmicro775
In this work, the three-dimensional structures of the uncomplexed proteinase 229E-HCoV 3CL and of TGEV 3CL-pro in complex with an inhibitor have been solved. On the basis of these structures, the authors provide a three-dimensional model of the main proteinase of SARS-CoV, and using molecular modelling, they suggest th...
10.1126/science.2971269
82,443,884
The study of human hematopoietic cells and the human immune system is hampered by the lack of a suitable experimental model. Experimental data are presented showing that human fetal liver hematopoietic cells, human fetal thymus, and human fetal lymph node support the differentiation of mature human T cells and B cells ...
10.1038/nrmicro2911
This is the first report to describe the engraftment of scid mice with human thymus and liver tissue to establish the scid -hu–Thy/Liv mouse model.
10.1126/science.3201256
81,425,101
SCID-hu mice with human fetal thymic or lymph node implants were inoculated with the cloned human immunodeficiency virus-1 isolate, HIV-1 JR-CSF . In a time- and dose-dependent fashion, viral replication spread within the human lymphoid organs. Combination immunohistochemistry and in situ hybridization revealed only vi...
10.1038/nrmicro2911
This study demonstrates productive HIV-1 infection and CD4 + T cell depletion in human tissues of hu- scid mice.
10.1182/blood-2001-12-0207
125,266,776
Abstract To establish a more appropriate animal recipient for xenotransplantation, NOD/SCID/γcnull mice double homozygous for the severe combined immunodeficiency (SCID) mutation and interleukin-2Rγ (IL-2Rγ) allelic mutation (γcnull) were generated by 8 backcross matings of C57BL/6J-γcnull mice and NOD/Shi-scidmice. Wh...
10.1038/nrmicro2911
This is one of the first reports to describe the development of a human immune system in NOD scid Il2gr −/− mice following engraftment with human CD34 + stem cells derived from cord blood.
10.4049/jimmunol.174.10.6477
82,881,735
Abstract Ethical considerations constrain the in vivo study of human hemopoietic stem cells (HSC). To overcome this limitation, small animal models of human HSC engraftment have been used. We report the development and characterization of a new genetic stock of IL-2R common γ-chain deficient NOD/LtSz-scid (NOD-scid IL2...
10.1038/nrmicro2911
This is an early study showing the development of a nearly complete human immune system following the engraftment of NOD scid Il2rg −/− mice with human CD34 + stem cells derived from peripheral blood.
10.1046/j.1365-2141.1998.00980.x
120,075,143
Xenotransplantation of human cells into immunodeficient mice has been used to develop models of human haemopoiesis and lymphoid cell function. However, the utility of existing mouse strains can be limited by shortened life‐spans, spontaneous production of functional lymphocytes with ageing, and residual innate immunity...
10.1038/nrmicro2911
This research demonstrates efficient engraftment of human CD34 + stem cells in Rag2 −/− Il2rg −/− mice, and shows the advantages of these mice over scid models.
10.1126/science.280.5362.427
62,286,495
Human and simian immunodeficiency virus (HIV and SIV) replicate optimally in activated memory CD4 + T cells, a cell type that is abundant in the intestine. SIV infection of rhesus monkeys resulted in profound and selective depletion of CD4 + T cells in the intestine within days of infection, before any such changes in ...
10.1038/nrmicro2911
This work identifies the GALT of rhesus macaques as a major site of SIV replication and CD4 + T cell depletion.
10.1073/pnas.0812587106
105,380,888
The lack of a primate model that utilizes HIV-1 as the challenge virus is an impediment to AIDS research; existing models generally employ simian viruses that are divergent from HIV-1, reducing their usefulness in preclinical investigations. Based on an understanding of species-specific variation in primate TRIM5 and A...
10.1038/nrmicro2911
This is an important proof-of-concept study demonstrating that a minimally modified strain of HIV-1, differing from HIV-1 only in vif , can replicate in pig-tailed macaques and is sensitive to a combination of antiretroviral drugs used to treat HIV-1 infection in humans.
10.1126/scitranslmed.3000524
19,625,808
This manuscript demonstrates unambiguous major histocompatibility complex heterozygote advantage in macaque monkeys infected with the same strain of simian immunodeficiency virus, suggesting that a prophylactic HIV vaccine should elicit a population of CD8 + T cells with broad specificity.
10.1038/nrmicro2911
This research makes elegant use of the limited number of MHC haplotypes in Mauritian cynomolgus macaques to demonstrate the heterozygote advantage in the control of SIV infection.
10.1126/science.3159089
28,251,092
The isolation of a T-cell tropic retrovirus from three immunodeficient macaques and one macaque with lymphoma is described. The morphology, growth characteristics, and antigenic properties of this virus indicate that it is related to the causative agent of acquired immune deficiency syndrome in humans (HTLV-III or LAV)...
10.1038/nrmicro2911
This is the first report to describe the isolation of SIV from rhesus macaques.
10.1126/science.2160735
103,304,678
Better understanding of the pathogenesis of acquired immunodeficiency syndrome (AIDS) would be greatly facilitated by a relevant animal model that uses molecularly cloned virus of defined sequence to induce the disease. Such a system would also be of great value for AIDS vaccine research. An infectious molecular clone ...
10.1038/nrmicro2911
This is the first study to show that an infectious molecular clone of SIV can cause AIDS in rhesus macaques.
10.1128/jvi.70.5.3198-3206.1996
40,527,503
To explore the roles played by specific human immunodeficiency virus type 1 (HIV-1) genes in determining the in vivo replicative capacity of AIDS viruses, we have examined the replication kinetics and virus-specific immune responses in rhesus monkeys following infection with two chimeric simian/human immunodeficiency v...
10.1038/nrmicro2911
This report describes the passage and initial isolation of the highly pathogenic chimaera SHIV89.6P.
10.1126/science.284.5415.816
17,840,167
Infection of macaques with chimeric simian–human immunodeficiency virus (SHIV) provides an excellent in vivo model for examining the influence of envelope on HIV-1 pathogenesis. Infection with a pathogenic CCR5 (R5)–specific enveloped virus, SHIV SF162P , was compared with infection with the CXCR4 (X4)–specific SHIV SF...
10.1038/nrmicro2911
This article describes the first pathogenic SHIV found to use CCR5 as a co-receptor.
10.1126/science.279.5348.237
67,544,412
Candidate mammalian odorant receptors were first cloned some 6 years ago. The physiological function of these receptors in initiating transduction in olfactory receptor neurons remains to be established. Here, a recombinant adenovirus was used to drive expression of a particular receptor gene in an increased number of ...
10.1038/nrn1365
First functional evidence that an OR determines responsiveness to a specific odorant.
10.1126/science.279.5349.338
100,832,594
Synaptic plasticity, the ability of neurons to alter the strength of their synaptic connections with activity and experience, is thought to play a critical role in memory storage. Molecular studies of gene expression during long-lasting synaptic plasticity related to memory storage initially focused on the identificati...
10.1038/nrn2572
This article reviews the role of negative regulators such as the transcriptional repressor CREB2 in synaptic plasticity and memory, with an emphasis on the removal of these constraints in memory storage.
10.1126/science.1321493
19,706,332
Although long-term potentiation (LTP) has been studied as the mechanism for hippocampus-dependent learning and memory, evidence for this hypothesis is still incomplete. The mice with a mutation in the α-calcium-calmodulin-dependent kinase II (α-CaMKII), a synaptic protein enriched in the hippocampus, are appropriate fo...
10.1038/nrn2572
The first paper demonstrating the use of genetic manipulations in the study of mechanisms of cognitive function in mammals.
10.1126/science.274.5293.1678
123,191,992
One of the major limitations in the use of genetically modified mice for studying cognitive functions is the lack of regional and temporal control of gene function. To overcome these limitations, a forebrain-specific promoter was combined with the tetracycline transactivator system to achieve both regional and temporal...
10.1038/nrn2572
This study introduced the inducible transgenic doxycycline system to the study of cognitive mechanisms and addressed the role of CaMKII in memory formation.
10.1126/science.1089845
41,196,113
The lasting effects of neuronal activity on brain development involve calcium-dependent gene expression. Using a strategy called transactivator trap, we cloned a calcium-responsive transactivator called CREST (for calcium-responsive transactivator). CREST is a SYT-related nuclear protein that interacts with adenosine 3...
10.1038/nrn2836
This paper documents the identification of CREST as a key mediator of activity-dependent dendritic growth.
10.1186/2040-2392-1-15
62,019,345
Abstract Background SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N -methyl-D-asp...
10.1038/nrn.2016.183
This study describes the first Shank3 -mutant mice (exon 4 and exon 9 deletion). These mice show some ASD-relevant phenotypes.
10.1126/science.1138389
41,682,339
Rett syndrome is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. However, neurons do not die, which suggests that this is not a neurodegenerative disorder. An important question for future therapeutic approaches to this and related disorders concerns pheno...
10.1038/nrn.2016.183
This study shows for the first time a robust phenotypic reversal, both in immature and in mature adult animal models of Rett syndrome, by induced expression of MeCP2.
10.1002/glia.21143
18,163,415
Abstract Malignant glioma is among of the most devastating, and least curable, types of cancer. Since the re‐emergence of the cancer stem cell hypothesis, much progress has been made towards elucidating the cellular origin of these tumors. The hypothesis that tumors are hierarchically organized, with a cancer stem cell...
10.1038/nrn3060
A comprehensive overview of the current thinking about the relationship between neural stem cells and progenitor cells, and their relationship to possible cells of origin for gliomas.
10.1002/acn3.136
105,377,802
Abstract Objective Brain involvement is a serious complication of HIV infection. The earliest changes in the brain, which represents an anatomic site for viral persistence, are largely unknown. Methods This investigation used quantitative Magnetic Resonance methodologies, including high resolution and diffusion tensor ...
10.1038/nrneurol.2016.27
This manuscript highlights neuroimaging and cerebrospinal fluid cytokine findings in primary HIV infection.
10.1002/ana.410190603
40,851,968
Abstract In order to define the histopathological substrate of the dementia that frequently complicates the acquired immune deficiency syndrome (AIDS), we analyzed the neuropathological findings in 70 autopsied adult AIDS patients, 46 of whom had suffered clinically overt dementia. Less than 10% of the brains were hist...
10.1038/nrneurol.2016.27
This classic clinicopathological patient series provided the first detailed descriptions of HIV-associated dementia, termed AIDS dementia complex.
10.1126/science.1105681
103,817,875
We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associate...
10.1038/nrn1788
A provocative paper showing that blocking axonal transport worsens symptoms in a mouse model of Alzheimer's disease. Results also suggested that axonal spheroids may be sites of APP processing into Aβ.
10.1111/j.1460-9568.1989.tb00771.x
29,188,162
Abstract Wallerian degeneration of the distal stump of a severed peripheral nerve involves invasion by myelomonocytic cells, whose presence is necessary for destruction of myelin and for initiating mitosis in Schwann cells (Beuche and Friede, 1984). Degeneration of the distal ends of the axons themselves is assumed to ...
10.1038/nrn1788
Reports the discovery of the slow Wallerian degeneration mutant ( Wld S ) mouse, which has done much to open up this field.
10.1073/pnas.90.5.1977
41,590,662
Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A...
10.1038/nrn2009
References 1 and 2 are the seminal papers that revealed the isoform-selective role of APOE in the development of late-onset AD.
10.1073/pnas.95.11.6460
62,564,838
The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer’s disease. During intracellular transport APP undergoes a series of proteolytic cleavages that lead to the release either of an amyloidogenic fragment called β-amyloid (Aβ) or of a nonamyloidogenic secreted form consisting of the ...
10.1038/nrn2009
The first report on the role of membrane cholesterol homeostasis in the regulation of Aβ peptide generation.
10.1126/science.294.5545.1354
125,149,448
The molecular mechanisms controlling synaptogenesis in the central nervous system (CNS) are poorly understood. Previous reports showed that a glia-derived factor strongly promotes synapse development in cultures of purified CNS neurons. Here, we identify this factor as cholesterol complexed to apolipoprotein E–containi...
10.1038/nrn2009
Reveals the role of cholesterol production and transport from glia to neurons for the generation of new synapses.
10.1073/pnas.0600316103
107,275,796
The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol mor...
10.1038/nrn2009
An original study that reveals the role of de novo cholesterol biosynthesis, pathway intermediates and turnover for synaptic neurotransmission in mouse brains.
10.1073/pnas.0600549103
19,035,630
The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synapto-dendritic connections, and scavenging toxins. In mult...
10.1038/nrn2009
An excellent review of potential mechanisms through which APOE * ε4 might cause neuropathology and AD.
10.1126/science.1065983
102,472,461
Protein-protein interactions and calcium entry through the N -methyl- d -aspartate (NMDA)–type glutamate receptor regulate synaptic development and plasticity in the central nervous system. The EphB receptor tyrosine kinases are localized at excitatory synapses where they cluster and associate with NMDA receptors. We i...
10.1038/nrn2009
Together with reference 116, this paper reports that Ephs and ephrins control NMDA receptor functions through mechanisms that resemble those involving reelin and APOE receptors.
10.1111/j.1468-1331.2009.02598.x
82,567,183
Background and purpose: It is well known that chronic inflammatory demyelinating polyneuropathy (CIDP) and diabetes mellitus (DM) are often associated, but it is not clear if these two disorders are patogenetically correlated. Methods: An epidemiological study on CIDP in two Italian regions (population 4 334 225) was p...
10.1038/nrneurol.2017.123
Italian epidemiological study that did not find an association of CIDP with diabetes.
10.1002/brb3.177
61,924,949
Abstract Background We have previously identified a subset of diabetic sensorimotor polyneuropathy ( DSP ) patients with probable demyelination related to poor glycemic control. We aimed to determine whether the clinical characteristics and electrodiagnostic classification of nerve injury in diabetes patients with “dem...
10.1038/nrneurol.2017.123
Study showing more severe neuropathy but better glycaemic control in patients with CIDP and diabetes, compared with patients with 'demyelinating' DSPN.
10.1242/dev.01429
125,211,966
Neural crest stem cells (NCSCs) persist in peripheral nerves throughout late gestation but their function is unknown. Current models of nerve development only consider the generation of Schwann cells from neural crest,but the presence of NCSCs raises the possibility of multilineage differentiation. We performed Cre-rec...
10.1038/nrn1746
Using Cre-recombinase technology, this study provides evidence that DHH + cells derived from embryonic mouse nerves give rise not only to Schwann cells but also to endoneurial fibroblasts.
10.1073/pnas.0831229100
60,708,709
In vertebrate embryos, diversification of the lineages arising from the neural crest (NC) is controlled to a large extent by environmental factors. In previous work, we showed that endothelin 3 (ET3) peptide favors the development of glial and melanocytic NC precursors in vitro . This factor is also capable of inducing...
10.1038/nrn1746
Shows that endothelin can induce Schwann cells derived from quail peripheral nerves to de-differentiate and give rise to both Schwann cells and melanocytes.
10.1101/gad.186601
83,442,590
The molecular mechanisms that determine glial cell fate in the vertebrate nervous system have not been elucidated. Peripheral glial cells differentiate from pluripotent neural crest cells. We show here that the transcription factor Sox10 is a key regulator in differentiation of peripheral glial cells. In mice that carr...
10.1038/nrn1746
Shows that SOX10 is required for the development of all peripheral glia.
10.1101/gad.12.12.1825
39,470,583
Neuregulins (NDF, heregulin, GGF ARIA, or SMDF) are EGF-like growth and differentiation factors that signal through tyrosine kinase receptors of the ErbB family. Here, we report a novel phenotype in mice with targeted mutations in the erbB2, erbB3, or neuregulin-1 genes. These three mutations cause a severe hypoplasia ...
10.1038/nrn1746
Establishes a requirement for NRG1 and its receptors ErbB2 and ErbB3 in the migration of neural crest cells to regions where sympathetic ganglia form.
10.1126/science.1095862
83,230,197
In the nervous system of vertebrates, myelination is essential for rapid and accurate impulse conduction. Myelin thickness depends on axon fiber size. We use mutant and transgenic mouse lines to show that axonal Neuregulin-1 (Nrg1) signals information about axon size to Schwann cells. Reduced Nrg1 expression causes hyp...
10.1038/nrn1746
The authors provide in vivo evidence of a role for β NRG late in development, namely in regulating myelin sheath thickness.
10.1073/pnas.97.14.7882
20,807,825
Functional signaling of endothelin 3 (ET3) and its receptor B (ETRB) has been shown to be required for the development of neural crest (NC)-derived pigment cells in mouse, but the precise role of ET3 is not completely understood. Using the avian embryo as a model, we previously reported that ET3 promotes the survival a...
10.1038/nrn1746
Shows that avian melanocytes can alter their differentiation programme in response to endothelin, leading them to generate both melanocytes and glia.
10.1083/jcb.200109021
83,444,853
In dystrophic mice, a model of merosin-deficient congenital muscular dystrophy, laminin-2 mutations produce peripheral nerve dysmyelination and render Schwann cells unable to sort bundles of axons. The laminin receptor and the mechanism through which dysmyelination and impaired sorting occur are unknown. We describe mi...
10.1038/nrn1746
The authors show that conditional ablation of β 1 integrin in developing Schwann cells causes severe defects in the process by which Schwann cells and axons segregate prior to myelination, although proliferation and cell death are unaffected.
10.1083/jcb.200307132
19,451,938
The transcription factor Krox-20 controls Schwann cell myelination. Schwann cells in Krox-20 null mice fail to myelinate, and unlike myelinating Schwann cells, continue to proliferate and are susceptible to death. We find that enforced Krox-20 expression in Schwann cells cell-autonomously inactivates the proliferative ...
10.1038/nrn1746
Shows that KROX20 inactivates Schwann cell proliferation in response to NRG1 and prevents cell death in response to TGFβ through inhibition of the JNK pathway. KROX20 also induces the expression of myelin genes in unrelated fibroblastic cells.
10.1101/gad.258203
41,582,453
The genetic hierarchy that controls myelination of peripheral nerves by Schwann cells includes the POU domain Oct-6/Scip/Tst-1and the zinc-finger Krox-20/Egr2 transcription factors. These pivotal transcription factors act to control the onset of myelination during development and tissue regeneration in adults following...
10.1038/nrn1746
Shows that in addition to the requirement for transcription factor OCT6 in controlling peripheral myelination, the related factor BRN2 also has a role.
10.1073/pnas.0913033107
98,181,410
We present a whole-proteome phylogeny of prokaryotes constructed by comparing feature frequency profiles (FFPs) of whole proteomes. Features are l -mers of amino acids, and each organism is represented by a profile of frequencies of all features. The selection of feature length is critical in the FFP method, and we hav...
10.1038/nrmicro2558
An interesting whole-proteome phylogeny study of prokaryotes that shows the Xanthomonadaceae family profiles clustered with the Betaproteobacteria.
10.1099/ijs.0.65220-0
58,414,918
The genus Xanthomonas currently comprises 27 species with validly published names that are important crop and horticultural pathogens. We have constructed a phylogram from alignment of gyrase B ( gyrB ) sequences for all xanthomonad species, both to indicate inter-species relatedness and as an aid for rapid and accurat...
10.1038/nrmicro2558
Highlights the complexity of the Xanthomonas spp. and details useful genetic tools for species discrimination.
10.1101/gr.3378705
40,378,819
Xanthomonas campestris pathovar campestris ( Xcc ) is the causative agent of crucifer black rot disease, which causes severe losses in agricultural yield world-wide. This bacterium is a model organism for studying plant-bacteria interactions. We sequenced the complete genome of Xcc 8004 (5,148,708 bp), which is highly ...
10.1038/nrmicro2558
An excellent study demonstrating the power of comparative and functional genomics to provide valuable information about Xanthomonas spp. pathogenicity.
10.1111/j.1364-3703.2009.00590.x
80,879,118
SUMMARY A review of type III effectors (T3 effectors) from strains of Xanthomonas reveals a growing list of candidate and known effectors based on functional assays and sequence and structural similarity searches of genomic data. We propose that the effectors and suspected effectors should be distributed into 39 so‐cal...
10.1038/nrmicro2558
A thorough review of type III effectors that are associated with Xanthomonas strains.
10.1111/j.1365-2958.2005.04961.x
45,319,545
Summary The bacterial pathogen Xanthomonas campestris pv. campestris ( Xcc ) recruits a diffusible signal factor (DSF), which has recently been structurally characterized as cis ‐11‐methyl‐2‐dodecenoic acid, as a cell–cell communication signal to synchronize virulence gene expression and biofilm dispersal. In this stud...
10.1038/nrmicro2558
An insightful study using the first oligomicroarray developed for Xanthomonas spp. to assess the effect of the DSF on gene expression in X. campestris
10.1073/pnas.0407383101
80,422,173
The bacterial pathogen Xanthomonas campestris pv. vesicatoria ( Xcv ) uses a type III secretion system (TTSS) to translocate effector proteins into host plant cells. The TTSS is required for Xcv colonization, yet the identity of many proteins translocated through this apparatus is not known. We used a genetic screen to...
10.1038/nrmicro2558
A description of an elegant functional screen for large-scale identification of type III effectors.
10.1105/tpc.108.058529
61,576,215
Abstract We demonstrate that XopD, a type III effector from Xanthomonas campestris pathovar vesicatoria (Xcv), suppresses symptom production during the late stages of infection in susceptible tomato (Solanum lycopersicum) leaves. XopD-dependent delay of tissue degeneration correlates with reduced chlorophyll loss, redu...
10.1038/nrmicro2558
This is the first description of the effector protein XopD, a cysteine protease with DNA-binding activity.
10.1083/jcb.200511054
82,304,243
Proper dialogue between presynaptic neurons and their targets is essential for correct synaptic assembly and function. At central synapses, Wnt proteins function as retrograde signals to regulate axon remodeling and the accumulation of presynaptic proteins. Loss of Wnt7a function leads to defects in the localization of...
10.1038/nrn2755
This manuscript shows that Wnt–Dishevelled signalling in presynaptic terminals regulates synaptic assembly and neurotransmitter release.
10.1146/annurev.pharmtox.44.101802.121631
61,509,076
New cells are continuously generated from immature proliferating cells throughout adulthood in many organs, thereby contributing to the integrity of the tissue under physiological conditions and to repair following injury. In contrast, repair mechanisms in the adult central nervous system (CNS) have long been thought t...
10.1038/nrn2755
Provides strong evidence that Wnt signalling is essential for adult hippocampal neurogenesis.
10.1111/j.1365-2958.2008.06294.x
45,315,101
Summary The export of proteins from their site of synthesis in the cytoplasm across the inner membrane is an important aspect of bacterial physiology. Because the location of extracytoplasmic proteins is ideal for host–pathogen interactions, protein export is also important to bacterial virulence. In bacteria, there ar...
10.1038/nrmicro2874
A review of SecA2 export, including a phylogenetic tree that depicts the evolutionary relationship of SecA2 proteins from both SecA2-only and SecA2–SecY2 systems.
10.1046/j.1365-2958.1998.00805.x
60,274,997
An adhesin of Streptococcus parasanguis FW213, a primary colonizer of the tooth surface, has been purified from the culture medium by immunoaffinity chromatography. The purified protein has a molecular mass of 200 kDa and stains positively for carbohydrate. The amino‐terminal sequence indicated that this protein repres...
10.1038/nrmicro2874
References 52 and 53 show that SecA2–SecY2 systems export proteins which are first glycosylated in the cytoplasm.
10.1111/j.1365-2958.2010.07346.x
100,339,787
Summary Bacterial binding to human platelets is an important step in the pathogenesis of infective endocarditis. Streptococcus gordonii can mediate its platelet attachment through a cell wall glycoprotein termed GspB (‘gordonii surface protein B’). GspB export is mediated by a seven‐component accessory Sec system, cont...
10.1038/nrmicro2874
The finding that glycosylation of a SecA2–SecY2 substrate blocks export by the canonical SecA1–SecYEG pathway.
10.1046/j.1365-2958.2002.03072.x
105,370,526
Summary We describe the identification and characterization of a second secA gene in Listeria monocytogenes . This gene, termed secA2 , is involved in smooth–rough phenotypic variation and secA2 expression contributes to bacterial virulence. Spontaneous rough (R‐) variants of L. monocytogenes grow in chains and form ro...
10.1038/nrmicro2874
The first description of SecA2 and an associated exported substrate in Listeria spp.
10.1242/dev.02254
16,665,467
During development, secreted signaling factors, called morphogens, instruct cells to adopt specific mature phenotypes. However, the mechanisms that morphogen systems employ to establish a precise concentration gradient for patterning tissue architecture are highly complex and are typically analyzed only at long times a...
10.1038/nrn3031
A model that analyses how the intricate transport and signal transduction mechanisms of a key morphogen, SHH, cooperate to regulate tissue patterning in the neural tube.
10.1038/msb.2010.51
60,419,117
Although there has been significant progress in understanding the molecular signals that change cell morphology, mechanisms that cells use to monitor their size and length to regulate their morphology remain elusive. Previous studies suggest that polarizing cultured hippocampal neurons can sense neurite length, identif...
10.1038/nrn3031
A combined modelling and experimental study showing that the dynamics of shootin 1, a key regulator of axon growth, constitutes a positive feedback loop that generates a signal for axon specification.
10.1073/pnas.0900715106
15,336,202
Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the mechanisms axons use to detect gradients are largely unknown. We first develop a Bayesian “ideal observer” analysis of gradient detection by axons, based on the hypothesis that a principal constraint on gradient dete...
10.1038/nrn3031
An optimal decision rule, by which a growth cone can most reliably extract gradient direction from its noisy receptors, predicts the response of axons to molecular gradients.
10.1126/science.1152677
38,319,829
We report that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived nerve growth factor (NGF) promoted expression of its own receptor TrkA in mouse and rat neurons ...
10.1038/nrn3031
A combined experimental and modelling study showing that target-derived nerve growth factor promotes expression of its own receptor and that this feedback loop is essential for the dynamics of competition.
10.1242/dev.02430
122,223,401
I present a novel analysis of abnormal retinocollicular maps in mice in which the distribution of EphA receptors over the retina has been modified by knockin and/or knockout of these receptor types. My analysis shows that in all these cases, whereas the maps themselves are discontinuous, the graded distribution of EphA...
10.1038/nrn3031
A computational model of topographic map formation in which the tectal gradient of ephrinA is induced by the retinal EphA gradient reproduces the variety of abnormal maps that are formed in EphA knock-in and/or knockout mice.
10.1152/jn.00704.2003
107,077,914
Determining the principles used to plan and execute movements is a fundamental question in neuroscience research. When humans reach to a target with their hand, they exhibit stereotypical movements that closely follow an optimally smooth trajectory. Even when faced with various perceptual or mechanical perturbations, s...
10.1038/nrn1427
This study illustrates how the motor system calculates state variables not only related to body motion, but also related to motion of grasped non-rigid objects.
10.1152/jn.00626.2002
62,244,881
We have used retrograde transneuronal transport of neurotropic viruses to examine the organization of the projections from the dentate nucleus of the cerebellum to “motor” and “nonmotor” areas of the cerebral cortex. To perform this analysis we created an unfolded map of the dentate. Plotting the results from current a...
10.1038/nrn1427
The use of retrograde transneuronal labelling with herpes virus from injections in different areas of the cerebral cortex shows that the dentate nucleus contains anatomically separate regions for motor and non-motor domains.
10.1126/science.298.5599.1790
20,784,188
N-linked protein glycosylation is the most abundant posttranslation modification of secretory proteins in eukaryotes. A wide range of functions are attributed to glycan structures covalently linked to asparagine residues within the asparagine-X-serine/threonine consensus sequence (Asn-Xaa-Ser/Thr). We found an N-linked...
10.1038/nrmicro2383
First study to demonstrate the use of bacteria for recombinant protein glyco-engineering.
10.1126/science.1134351
59,267,620
N-linked protein glycosylation is found in all domains of life. In eukaryotes, it is the most abundant protein modification of secretory and membrane proteins, and the process is coupled to protein translocation and folding. We found that in bacteria, N-glycosylation can occur independently of the protein translocation...
10.1038/nrmicro2383
Study showing that, in contrast to the glycosylation of unfolded proteins in eukaryotes, N -glycosylation in bacteria occurs at locally flexible structures in folded proteins.
10.1073/pnas.0507311102
62,570,869
Campylobacter jejuni has a general N-linked glycosylation pathway (encoded by the pgl gene cluster), which culminates in the transfer of a heptasaccharide: GalNAc-α1,4-GalNAc-α1,4-(Glcβ1,3)-GalNAc-α1,4-GalNAc-α1,4-GalNAc-α1,3-Bac [where Bac is bacillosamine (2,4-diacetamido-2,4,6-trideoxyglucose)] from a membrane-ancho...
10.1038/nrmicro2383
First in vitro synthesis of the complete lipid-linked N -glycan of C. jejuni using purified enzyme components and chemically synthesized Und-PP-diNAcBac.
10.1128/jb.00211-10
101,116,498
ABSTRACT The first bacterial N-linked glycosylation system was discovered in Campylobacter jejuni , and the key enzyme involved in the coupling of glycan to asparagine residues within the acceptor sequon of the glycoprotein is the oligosaccharyltransferase PglB. Emerging genome sequence data have revealed that pglB ort...
10.1038/nrmicro2383
Description of another bacterial N -glycosylation pathway resembling the C. jejuni prototype.
10.1073/pnas.0809504106
103,926,953
Protein glycosylation is an important element of biologic systems because of its significant effects on protein properties and functions. Although prominent within all domains of life, O-linked glycosylation systems modifying serine and threonine residues within bacteria and eukaryotes differ substantially in target pr...
10.1038/nrmicro2383
Demonstration of general protein O -glycosylation in Neisseria spp., along with reference 116.
10.1073/pnas.0903078106
28,083,432
The food-borne pathogen Campylobacter jejuni is one of the leading causes of bacterial gastroenteritis worldwide and the most frequent antecedent in neuropathies such as the Guillain-Barré and Miller Fisher syndromes. C. jejuni was demonstrated to possess an N -linked protein glycosylation pathway that adds a conserved...
10.1038/nrmicro2383
Demonstration that PglB of C. jejuni possesses both OTase and hydrolase activity and that release of fOS is sensitive to osmolyte concentration.