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source_doi stringlengths 13 57	source_mag_paper_id int64 490k 157M	source_abstract stringlengths 8 10.7k	target_doi stringlengths 14 27	target_summary stringlengths 42 889
10.1073/pnas.91.7.2757	107,202,074	The origin and taxonomic status of domesticated cattle are controversial. Zebu and taurine breeds are differentiated primarily by the presence or absence of a hump and have been recognized as separate species (Bos indicus and Bos taurus). However, the most widely held view is that both types of cattle derive from a single domestication event 8000-10,000 years ago. We have examined mtDNA sequences from representatives of six European (taurine) breeds, three Indian (zebu) breeds, and four African (three zebu, one taurine) breeds. Similar levels of average sequence divergence were observed among animals within each of the major continental groups: 0.41% (European), 0.38% (African), and 0.42% (Indian). However, the sequences fell into two very distinct geographic lineages that do not correspond with the taurine-zebu dichotomy: all European and African breeds are in one lineage, and all Indian breeds are in the other. There was little indication of breed clustering within either lineage. Application of a molecular clock suggests that the two major mtDNA clades diverged at least 200,000, and possibly as much as 1 million, years ago. This relatively large divergence is interpreted most simply as evidence for two separate domestication events, presumably of different subspecies of the aurochs, Bos primigenius. The clustering of all African zebu mtDNA sequences within the taurine lineage is attributed to ancestral crossbreeding with the earlier B. taurus inhabitants of the continent.	10.1038/35052563	A demonstration that cattle have been domesticated from two distinct subspecies and that many breeds of African cattle are hybrids between the two owing to male-derived gene flow.
10.1093/genetics/154.4.1785	83,366,887	Abstract The domestic pig originates from the Eurasian wild boar (Sus scrofa). We have sequenced mitochondrial DNA and nuclear genes from wild and domestic pigs from Asia and Europe. Clear evidence was obtained for domestication to have occurred independently from wild boar subspecies in Europe and Asia. The time since divergence of the ancestral forms was estimated at ~500,000 years, well before domestication ~9,000 years ago. Historical records indicate that Asian pigs were introduced into Europe during the 18th and early 19th centuries. We found molecular evidence for this introgression and the data indicated a hybrid origin of some major “European” pig breeds. The study is an advance in pig genetics and has important implications for the maintenance and utilization of genetic diversity in this livestock species.	10.1038/35052563	Evidence is presented for independent domestication of Wild Boar subspecies in Europe and Asia.
10.1073/pnas.96.16.9252	122,095,374	We previously mapped a quantitative trait locus (QTL) affecting milk production to bovine chromosome 14. To refine the map position of this QTL, we have increased the density of the genetic map of BTA14q11–16 by addition of nine microsatellites and three single nucleotide polymorphisms. Fine-mapping of the QTL was accomplished by a two-tiered approach. In the first phase, we identified seven sires heterozygous “ Qq ” for the QTL by marker-assisted segregation analysis in a Holstein-Friesian pedigree comprising 1,158 individuals. In a second phase, we genotyped the seven selected sires for the newly developed high-density marker map and searched for a shared haplotype flanking an hypothetical, identical-by-descent QTL allele with large substitution effect. The seven chromosomes increasing milk fat percentage were indeed shown to carry a common chromosome segment with an estimated size of 5 cM predicted to contain the studied QTL. The same haplotype was shown to be associated with increased fat percentage in the general population as well, providing additional support in favor of the location of the QTL within the corresponding interval.	10.1038/35052563	This paper shows how the identity-by-descent approach can be applied to high-resolution mapping of quantitative trait loci in farm animals by using extensive pedigree information.
10.1101/gr.10.2.220	100,831,446	A genome-wide linkage disequilibrium (LD) map was generated using microsatellite genotypes (284 autosomal microsatellite loci) of 581 gametes sampled from the dutch black-and-white dairy cattle population. LD was measured between all marker pairs, both syntenic and nonsyntenic. Analysis of syntenic pairs revealed surprisingly high levels of LD that, although more pronounced for closely linked marker pairs, extended over several tens of centimorgan. In addition, significant gametic associations were also shown to be very common between nonsyntenic loci. Simulations using the known genealogies of the studied sample indicate that random drift alone is likely to account for most of the observed disequilibrium. No clear evidence was obtained for a direct effect of selection (“Bulmer effect”). The observation of long range disequilibrium between syntenic loci using low-density marker maps indicates that LD mapping has the potential to be very effective in livestock populations. The frequent occurrence of gametic associations between nonsyntenic loci, however, encourages the combined use of linkage and linkage disequilibrium methods to avoid false positive results when mapping genes in livestock.	10.1038/35052563	The pattern of linkage disequilibrium (LD) across the genome in dairy cattle is evaluated. The strong LD detected holds promise that LD mapping will be a powerful strategy for mapping quantitative trait loci in farm animals.
10.1126/science.8134840	17,452,622	The European wild boar was crossed with the domesticated Large White pig to genetically dissect phenotypic differences between these populations for growth and fat deposition. The most important effects were clustered on chromosome 4, with a single region accounting for a large part of the breed difference in growth rate, fatness, and length of the small intestine. The study is an advance in genome analyses and documents the usefulness of crosses between divergent outbred populations for the detection and characterization of quantitative trait loci. The genetic mapping of a major locus for fat deposition in the pig could have implications for understanding human obesity.	10.1038/35052563	The first paper to show the use of divergent intercrosses for mapping quantitative trait loci in outbred populations.
10.1126/science.288.5469.1248	82,411,367	A high proportion of purebred Hampshire pigs carries the dominant RN − mutation, which causes high glycogen content in skeletal muscle. The mutation has beneficial effects on meat content but detrimental effects on processing yield. Here, it is shown that the mutation is a nonconservative substitution (R200Q) in the PRKAG3 gene, which encodes a muscle-specific isoform of the regulatory γ subunit of adenosine monophosphate–activated protein kinase (AMPK). Loss-of-function mutations in the homologous gene in yeast ( SNF4 ) cause defects in glucose metabolism, including glycogen storage. Further analysis of the PRKAG3 signaling pathway may provide insights into muscle physiology as well as the pathogenesis of noninsulin-dependent diabetes mellitus in humans, a metabolic disorder associated with impaired glycogen synthesis.	10.1038/35052563	The first positional cloning of a trait locus in a farm animal. Linkage mapping, linkage disequilibrium mapping, radiation hybrid mapping, construction of a BAC contig, BAC sequencing and bioinformatic analysis eventually resulted in the identification of the causative missense mutation.
10.1126/science.1862346	62,290,298	Malignant hyperthermia (MH) causes neurological, liver, and kidney damage and death in humans and major economic losses in the swine industry. A single point mutation in the porcine gene for the skeletal muscle ryanodine receptor ( ryr1 ) was found to be correlated with MH in five major breeds of lean, heavily muscled swine. Haplotyping suggests that the mutation in all five breeds has a common origin. Assuming that this is the causal mutation for MH, the development of a noninvasive diagnostic test will provide the basis for elimination of the MH gene or its controlled inclusion in swine breeding programs.	10.1038/35052563	The first molecular description of a major trait locus in farm animals.
10.1083/jcb.153.2.397	58,551,536	The correct positioning of the nucleus is often important in defining the spatial organization of the cell, for example, in determining the cell division plane. In interphase Schizosaccharomyces pombe cells, the nucleus is positioned in the middle of the cylindrical cell in an active microtubule (MT)-dependent process. Here, we used green fluorescent protein markers to examine the dynamics of MTs, spindle pole body, and the nuclear envelope in living cells. We find that interphase MTs are organized in three to four antiparallel MT bundles arranged along the long axis of the cell, with MT plus ends facing both the cell tips and minus ends near the middle of the cell. The MT bundles are organized from medial MT-organizing centers that may function as nuclear attachment sites. When MTs grow to the cell tips, they exert transient forces produced by plus end MT polymerization that push the nucleus. After an average of 1.5 min of growth at the cell tip, MT plus ends exhibit catastrophe and shrink back to the nuclear region before growing back to the cell tip. Computer modeling suggests that a balance of these pushing MT forces can provide a mechanism to position the nucleus at the middle of the cell.	10.1038/35089520	Using live imaging and computer simulation these authors have shown that the interphase nucleus can be maintained in the centre of the cell by a balance between pushing forces generating by microtubules.
10.1101/gad.14.6.690	131,922,988	E2F is a family of transcription factors that regulate both cellular proliferation and differentiation. To establish the role of E2F3 in vivo, we generated an E2f3 mutant mouse strain. E2F3-deficient mice arise at one-quarter of the expected frequency, demonstrating that E2F3 is important for normal development. To determine the molecular consequences of E2F3 deficiency, we analyzed the properties of embryonic fibroblasts derived from E2f3 mutant mice. Mutation of E2f3 dramatically impairs the mitogen-induced, transcriptional activation of numerous E2F-responsive genes. We have been able to identify a number of genes, including B-myb , cyclin A , cdc2 , cdc6 , and DHFR , whose expression is dependent on the presence of E2F3 but not E2F1. We further show that a critical threshold level of one or more of the E2F3-regulated genes determines the timing of the G 1 /S transition, the rate of DNA synthesis, and thereby the rate of cellular proliferation. Finally, we show that E2F3 is not required for cellular immortalization but is rate limiting for the proliferation of the resulting tumor cell lines. We conclude that E2F3 is critical for the transcriptional activation of genes that control the rate of proliferation of both primary and tumor cells.	10.1038/35096061	Disruption of mouse E2f3 , but not E2f1 , reduces transcription of E2f-responsive genes and retards entry into S phase.
10.1073/pnas.171217498	2,697,763	Establishment of cell lines from primary mouse embryo fibroblasts depends on loss of either the Arf tumor suppressor or its downstream target, the p53 transcription factor. Mouse p19 Arf is encoded by the Ink4a-Arf locus, which also specifies a second tumor suppressor protein, the cyclin D-dependent kinase inhibitor p16 Ink4a . We surveyed bone marrow-derived cells from wild-type, Ink4a-Arf -null, or Arf -null mice for their ability to bypass senescence during continuous passage in culture. Unlike preB cells from wild-type mice, those from mice lacking Arf alone could be propagated indefinitely when placed onto stromal feeder layers engineered to produce IL-7. The preB cell lines remained diploid and IL-7-dependent and continued to express elevated levels of p16 Ink4a . By contrast, Arf -null bone marrow-derived macrophages that depend on colony-stimulating factor-1 for proliferation and survival in culture initially grew at a slow rate but gave rise to rapidly and continuously growing, but still growth factor-dependent, variants that ceased to express p16 Ink4a . Wild-type bone marrow-derived macrophages initially expressed both p16 Ink4a and p19 Arf but exhibited an extended life span when p16 Ink4a expression was extinguished. In all cases, gene silencing was accompanied by methylation of the Ink4a promoter. Therefore, whereas Arf loss alone appears to be the major determinant of establishment of murine fibroblast and preB cell lines in culture, p16 Ink4a provides an effective barrier to immortalization of bone marrow-derived macrophages.	10.1038/35096061	Like MEFs, mouse bone-marrow-derived pre-B cells that lack Arf are immortal, whereas bone-marrow-derived macrophages must also silence the Ink4a gene to become established as continuously growing cell lines.
10.1101/gad.859201	18,000,382	Telomere shortening is the mechanism underlying replicative aging in fibroblasts. A variety of reports now claim that inactivation of the p16 INK4a /pRB pathway is required in addition to telomere maintenance for the immortalization of cells such as skin keratinocytes and breast epithelial cells. We here show that the premature growth arrest of these cell types can be explained by an inadequate culture environment. Providing mesenchymal/epithelial interactions by cultivating the telomerase-expressing cells on feeder layers avoids the growth arrest associated with increased p16 INK4a . These results do not support a telomere-independent mechanism of replicative aging.	10.1038/35096061	Growing primary human keratinocytes and mammary epithelial cells over feeder layers in defined medium can prevent induction of p16 Ink4a and enable their immortalization by introducing the telomerase catalytic subunit.
10.1073/pnas.97.7.3266	2,550,721	p19ARF has been implicated as a key regulator of p53 stability and activation. While numerous stresses activate the p53 growth arrest pathway, those requiring p19ARF remain to be elucidated. We used p19ARF knockout mouse embryo fibroblasts to show that DNA damage and microtubule disruption require p19ARF to induce p53 responses, whereas ribonucleotide depletion and inhibition of RNA synthesis by low doses of actinomycin D do not. The data provide evidence that the arrest pathway activated by ribonucleotide depletion involves some different signal transducers than those activated by DNA damage or microtubule disruption. We also present biochemical analyses that provide insights into the mechanism by which p53 and p19ARF cooperate in normal cells to induce cell cycle arrest.	10.1038/35096061	DNA damage activates p53 through both Arf -independent and Arf -dependent signalling pathways, so Arf loss affects the durability of the DNA-damage response.
10.1101/gad.893201	58,557,849	In Saccharomyces cerevisiae , Pds1 is an anaphase inhibitor and plays an essential role in DNA damage and spindle checkpoint pathways. Pds1 is phosphorylated in response to DNA damage but not spindle disruption, indicating distinct mechanisms delaying anaphase entry. Phosphorylation of Pds1 is Mec1 and Chk1 dependent in vivo. Here, we show that Pds1 is phosphorylated at multiple sites in vivo in response to DNA damage by Chk1. Mutation of the Chk1 phosphorylation sites on Pds1 abolished most of its DNA damage–inducible phosphorylation and its checkpoint function, whereas its anaphase inhibitor functions and spindle checkpoint functions remain intact. Loss of Pds1 phosphorylation correlates with APC-dependent Pds1 destruction in response to DNA damage. We also show that APC Cdc20 is active in preanaphase arrested cells after DNA damage. This suggests that Pds1 is stabilized by phosphorylation in response to DNA damage, but APC Cdc20 activity is not altered. Our results indicate that phosphorylation of Pds1 by Chk1 is the key function of Chk1 required to prevent anaphase entry.	10.1038/35096061	The Atm kinase phosphorylates E2f1, enhancing its activity. This indicates a novel mechanism by which ATM might induce p53.
10.1101/gad.827300	62,564,950	The p19 ARF tumor suppressor antagonizes Mdm2 to induce p53-dependent cell cycle arrest. Individual TKO (triple knock out) mice nullizygous for ARF, p53 , and Mdm2 develop multiple tumors at a frequency greater than those observed in animals lacking both p53 and Mdm2 or p53 alone, demonstrating that p19 ARF can act independently of the Mdm2-p53 axis in tumor surveillance. Reintroduction of ARF into TKO mouse embryo fibroblasts (MEFs), but not into those lacking both p53 and ARF , arrested the cell division cycle in the G1 phase. Inhibition of the retinoblastoma protein had no effect on the ability of ARF to arrest TKO MEFs. Thus, in the absence of Mdm2, p19 ARF interacts with other targets to inhibit cell proliferation.	10.1038/35096061	Mice lacking Arf Mdm2 and p53 show a broader spectrum of tumours than those lacking Mdm2 and p53 . Introduction of p19 Arf into primary MEFs that lack Arf Mdm2 and p53 induces G1 arrest, albeit slowly. Arf must interact with proteins other than Mdm2.
10.1101/gad.813600	41,544,935	The very late-flowering behavior of Arabidopsis winter-annual ecotypes is conferred mainly by two genes, FRIGIDA ( FRI ) and FLOWERING LOCUS C ( FLC ). A MADS-domain gene, AGAMOUS-LIKE 20 ( AGL20 ), was identified as a dominant FRI suppressor in activation tagging mutagenesis. Overexpression of AGL20 suppresses not only the late flowering of plants that have functional FRI and FLC alleles but also the delayed phase transitions during the vegetative stages of plant development. Interestingly, AGL20 expression is positively regulated not only by the redundant vernalization and autonomous pathways of flowering but also by the photoperiod pathway. Our results indicate that AGL20 is an important integrator of three pathways controlling flowering in Arabidopsis .	10.1038/35056041	A gain-of-function allele of SOC1 was identified as a suppressor of the late-flowering phenotype of frigida fri ) mutants. SOC1 is regulated by all three flowering-time pathways.
10.1126/science.288.5471.1613	20,764,232	In plants, flowering is triggered by endogenous and environmental signals. CONSTANS (CO) promotes flowering of Arabidopsis in response to day length. Four early target genes of CO were identified using a steroid-inducible version of the protein. Two of these genes, SUPPRESSOR OF OVEREXPRESSION OF CO 1 ( SOC1 ) and FLOWERING LOCUS T ( FT ), are required for CO to promote flowering; the others are involved in proline or ethylene biosynthesis. The SOC1 and FT genes are also regulated by a second flowering-time pathway that acts independently of CO. Thus, early target genes of CO define common components of distinct flowering-time pathways.	10.1038/35056041	SOC1 , a previously uncharacterized MADS-box gene, was identified as one of four CO target genes. Both SOC1 and FLOWERING LOCUS T FT ) are shown to be positively regulated by CO and negatively regulated by FLC
10.1073/pnas.96.13.7342	122,468,672	The evolutionary origin of the angiosperms (flowering plants sensu stricto ) is still enigmatic. Answers to the question of angiosperm origins are intimately connected to the identification of their sister group among extinct and extant taxa. Most phylogenetic analyses based on morphological data agree that among the groups of extant seed plants, the gnetophytes are the sister group of the angiosperms. According to this view, angiosperms and gnetophytes are the only extant members of a clade called “anthophytes” to emphasize their shared possession of flower-like reproductive structures. However, most phylogeny reconstructions based on molecular data so far did not support an anthophyte clade, but also could not clarify the case because support for alternative groupings has been weak or controversial. We have isolated 13 different homologs of MADS-type floral homeotic genes from the gnetophyte Gnetum gnemon . Five of these genes fall into monophyletic gene clades also comprising putatively orthologous genes from flowering plants and conifers, among them orthologs of floral homeotic B and C function genes. Within these clades the Gnetum genes always form distinct subclades together with the respective conifer genes, to the exclusion of the angiosperm genes. This provides strong molecular evidence for a sister-group relationship between gnetophytes and conifers, which is in contradiction to widely accepted interpretations of morphological data for almost a century. Our phylogeny reconstructions and the outcome of expression studies suggest that complex features such as flower-like reproductive structures and double-fertilization arose independently in gnetophytes and angiosperms.	10.1038/35056041	This paper describes phylogenetic studies of B-function MADS-box gene orthologues in gymnosperms and angiosperms, and concludes that Gnetales are more closely related to gymnosperms than to angiosperms (see also references 69 70 108 109
10.1073/pnas.97.8.4086	79,469,265	Phylogenetic relationships among the five groups of extant seed plants are presently quite unclear. For example, morphological studies consistently identify the Gnetales as the extant sister group to angiosperms (the so-called “anthophyte” hypothesis), whereas a number of molecular studies recover gymnosperm monophyly, and few agree with the morphology-based placement of Gnetales. To better resolve these and other unsettled issues, we have generated a new molecular data set of mitochondrial small subunit rRNA sequences, and have analyzed these data together with comparable data sets for the nuclear small subunit rRNA gene and the chloroplast rbcL gene. All nuclear analyses strongly ally Gnetales with a monophyletic conifers, whereas all mitochondrial analyses and those chloroplast analyses that take into account saturation of third-codon position transitions actually place Gnetales within conifers, as the sister group to the Pinaceae. Combined analyses of all three genes strongly support this latter relationship, which to our knowledge has never been suggested before. The combined analyses also strongly support monophyly of extant gymnosperms, with cycads identified as the basal-most group of gymnosperms, Ginkgo as the next basal, and all conifers except for Pinaceae as sister to the Gnetales + Pinaceae clade. According to these findings, the Gnetales may be viewed as extremely divergent conifers, and the many morphological similarities between angiosperms and Gnetales (e.g., double fertilization and flower-like reproductive structures) arose independently.	10.1038/35056041	References 115 and 116 present the phylogenetic trees of mitochondrial, plastid and nuclear genes from gymnosperms and angiosperms. The authors conclude that Gnetales are closely related to gymnosperms (see also references 69 70 105
10.1242/dev.125.18.3635	41,650,361	The anterior-posterior axis of Drosophila originates from two symmetry-breaking steps during early oogenesis. First, one of the two pro-oocytes within the cyst of 16 germline cells is selected to become the oocyte. This cell then comes to lie posterior to the other germline cells of the cyst, thereby defining the polarity of the axis. Here we show that the oocyte reaches the posterior of the cyst in two steps. (1) The cyst flattens as it enters region 2b of the germarium to place the two pro-oocytes in the centre of the cyst, where they contact the posterior follicle cells. (2) One cell is selected to become the oocyte and protrudes into the posterior follicle cell layer when the cyst rounds up on entering region 3. During this germ cell rearrangement, the components of the homophilic cadherin adhesion complex, DE-cadherin, Armadillo and alpha-catenin, accumulate along the border between the oocyte and the posterior follicle cells. Furthermore, the positioning of the oocyte requires cadherin-dependent adhesion between these two cell types, since the oocyte is frequently misplaced when DE-cadherin is removed from either the germline or the posterior follicle cells. We conclude that the oocyte reaches the posterior of the germline cyst because it adheres more strongly to the posterior follicle cells than its neighbours during the germ cell rearrangement that occurs as the cyst moves into region 3. The Drosophila anterior-posterior axis therefore becomes polarised by an unusual cadherin-mediated adhesion between a germ cell and mesodermal follicle cells.	10.1038/35038540	References 11 and 12 show that cadherin-mediated interactions between follicle cells and the oocyte are essential for oocyte positioning.
10.1093/oso/9780195099713.001.0001	125,276,793	This book presents a unified view of evolutionary algorithms: the exciting new probabilistic search tools inspired by biological models that have immense potential as practical problem-solvers in a wide variety of settings, academic, commercial, and industrial. In this work, the author compares the three most prominent representatives of evolutionary algorithms: genetic algorithms, evolution strategies, and evolutionary programming. The algorithms are presented within a unified framework, thereby clarifying the similarities and differences of these methods. The author also presents new results regarding the role of mutation and selection in genetic algorithms, showing how mutation seems to be much more important for the performance of genetic algorithms than usually assumed. The interaction of selection and mutation, and the impact of the binary code are further topics of interest. Some of the theoretical results are also confirmed by performing an experiment in meta-evolution on a parallel computer. The meta-algorithm used in this experiment combines components from evolution strategies and genetic algorithms to yield a hybrid capable of handling mixed integer optimization problems. As a detailed description of the algorithms, with practical guidelines for usage and implementation, this work will interest a wide range of researchers in computer science and engineering disciplines, as well as graduate students in these fields.	10.1038/35076523	Survey of all evolutionary computation types, with mathematical characterization of their properties
10.1162/evco.1998.6.2.109	82,987,539	The paper is in three parts. First, we use simple adversary arguments to redevelop and explore some of the no-free-lunch (NFL) theorems and perhaps extend them a little. Second, we clarify the relationship of NFL theorems to algorithm theory and complexity classes such as NP. We claim that NFL is weaker in the sense that the constraints implied by the conjectures of traditional algorithm theory on what an evolutionary algorithm may be expected to accomplish are far more severe than those implied by NFL. Third, we take a brief look at how natural evolution relates to computation and optimization. We suggest that the evolution of complex systems exhibiting high degrees of orderliness is not equivalent in difficulty to optimizing hard (in the complexity sense) problems, and that the optimism in genetic algorithms (GAs) as universal optimizers is not justified by natural evolution. This is an informal tutorial paper—most of the information presented is not formally proven, and is either “common knowledge” or formally proven elsewhere. Some of the claims are intuitions based on experience with algorithms, and in a more formal setting should be classified as conjectures.	10.1038/35076523	Readable presentation of 'no free lunch' theorems, an important part of evolutionary computation theory
10.1146/annurev.immunol.19.1.197	83,284,251	Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3ζ, Fc∍RIγ, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR dull phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.	10.1038/35095564	A comprehensive review of the NKp30, NKp44 and NKp46 receptors and their potential role in tumour recognition.
10.1126/science.290.5489.84	39,451,629	With the detailed description and analysis of several inhibitory receptor systems on lymphoid and myeloid cells, a central paradigm has emerged in which the pairing of activation and inhibition is necessary to initiate, amplify, and then terminate immune responses. In some cases, the activating and inhibitory receptors recognize similar ligands, and the net outcome is determined by the relative strength of these opposing signals. The importance of this modulation is demonstrated by the sometimes fatal autoimmune disorders observed in mice with targeted disruption of inhibitory receptors. The significance of these receptors is further evidenced by the conservation of immunoreceptor tyrosine-based inhibitory motifs during their evolution.	10.1038/35095564	A comprehensive review of the inhibitory immune receptors, including the MHC class I receptors that regulate natural killer cells and T-cell activation.
10.1126/science.285.5428.727	125,332,529	Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for γδ T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most γδ T cells, CD8 + αβ T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of γδ T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.	10.1038/35095564	Shows that the NKG2D receptor binds to the stress-induced MIC molecules and activates natural killer cells.
10.1126/science.285.5428.730	18,898,701	Many immune receptors are composed of separate ligand-binding and signal-transducing subunits. In natural killer (NK) and T cells, DAP10 was identified as a cell surface adaptor protein in an activating receptor complex with NKG2D, a receptor for the stress-inducible and tumor-associated major histocompatibility complex molecule MICA. Within the DAP10 cytoplasmic domain, an Src homology 2 (SH2) domain–binding site was capable of recruiting the p85 subunit of the phosphatidylinositol 3-kinase (PI 3-kinase), providing for NKG2D-dependent signal transduction. Thus, NKG2D-DAP10 receptor complexes may activate NK and T cell responses against MICA-bearing tumors.	10.1038/35095564	Shows that the NKG2D receptor signals through a transmembrane adaptor molecule activating the phosphatidylinositol 3-kinase pathway.
10.1073/pnas.93.22.12445	122,696,422	Conventional major histocompatibility complex (MHC) class I genes encode molecules that present intracellular peptide antigens to T cells. They are ubiquitously expressed and regulated by interferon gamma. Two highly divergent human MHC class I genes, MICA and MICB, are regulated by promoter heat shock elements similar to those of HSP70 genes. MICA encodes a cell surface glycoprotein, which is not associated with beta 2-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium. Thus, this MHC class I molecule may function as an indicator of cell stress and may be recognized by a subset of gut mucosal T cells in an unusual interaction.	10.1038/35095564	Reports that the MIC genes are regulated by stress and that MIC-bearing cells are recognized by γδ-TcR + T cells.
10.1073/pnas.96.12.6879	62,489,700	Human MHC class I-related molecules, MICA and MICB, are stress-induced antigens that are recognized by a subset of γδ T cells expressing the variable region V δ 1. This functional association has been found to be limited to intestinal epithelium, where these T cells are prevalent and where MICA and, presumably, MICB are mainly expressed. However, increased frequencies of V δ 1 γδ T cells have been observed in various epithelial tumors; moreover, MICA/B are expressed on diverse cultured epithelial tumor cells. With freshly isolated tumor specimens, expression of MICA/B was documented in many, but not all, carcinomas of the lung, breast, kidney, ovary, prostate, and colon. In tumors that were positive for MICA/B, the frequencies of V δ 1 γδ T cells were significantly higher than in those that were negative. V δ 1 γδ T cell lines and clones derived from different tumors recognized MICA/B on autologous and heterologous tumor cells. In accord with previous evidence, no constraints were observed in these interactions, such as those imposed by specific peptide ligands. Thus, MICA/B are tumor-associated antigens that can be recognized, in an apparently unconditional manner, by a subset of tumor-infiltrating γδ T cells. These results raise the possibility that an induced expression of MICA/B, by conditions that may be related to tumor homeostasis and growth, could play a role in immune responses against tumors.	10.1038/35095564	MICA and MICB are overexpressed on primary human tumours, providing targets for the immune system.
10.1126/science.287.5455.1031	123,838,104	The nonclassical major histocompatibility complex (MHC) class I molecule HLA-E inhibits natural killer (NK) cell–mediated lysis by interacting with CD94/NKG2A receptors. Surface expression of HLA-E depends on binding of conserved peptides derived from MHC class I molecules. The same peptide is present in the leader sequence of the human cytomegalovirus (HCMV) glycoprotein UL40 (gpUL40). It is shown that, independently of the transporter associated with antigen processing, gpUL40 can up-regulate expression of HLA-E, which protects targets from NK cell lysis. While classical MHC class I molecules are down-regulated, HLA-E is up-regulated by HCMV. Induction of HLA-E surface expression by gpUL40 may represent an escape route for HCMV.	10.1038/35095564	Reports that the leader segment of human cytomegalovirus protein UL40 binds to human leukocyte antigen-E and protects cells from lysis by natural killer cells bearing the CD94/NKG2A inhibitory receptor.
10.1073/pnas.95.3.1148	19,539,739	The Belgrade ( b ) rat has an autosomal recessively inherited, microcytic, hypochromic anemia associated with abnormal reticulocyte iron uptake and gastrointestinal iron absorption. The b reticulocyte defect appears to be failure of iron transport out of endosomes within the transferrin cycle. Aspects of this phenotype are similar to those reported for the microcytic anemia ( mk ) mutation in the mouse. Recently, mk has been attributed to a missense mutation in the gene encoding the putative iron transporter protein Nramp2. To investigate the possibility that Nramp2 was also mutated in the b rat, we established linkage of the phenotype to the centromeric portion of rat chromosome 7. This region exhibits synteny to the chromosomal location of Nramp2 in the mouse. A polymorphism within the rat Nramp2 gene cosegregated with the b phenotype. A glycine-to-arginine missense mutation (G185R) was present in the b Nramp2 gene, but not in the normal allele. Strikingly, this amino acid alteration is the same as that seen in the mk mouse. Functional studies of the protein encoded by the b allele of rat Nramp2 demonstrated that the mutation disrupted iron transport. These results confirm the hypothesis that Nramp2 is the protein defective in the Belgrade rat and raise the possibility that the phenotype shared by mk and b animals is unique to the G185R mutation. Furthermore, the phenotypic characteristics of these animals indicate that Nramp2 is essential both for normal intestinal iron absorption and for transport of iron out of the transferrin cycle endosome.	10.1038/35042073	By identifying a mutation in the b rat, DMT1 was shown to transport iron into and out of endosomes.
10.1182/blood.v94.1.9.413a43_9_11	121,592,407	Targeted mutagenesis was used to produce two mutations in the murine hemochromatosis gene (Hfe) locus. The first mutation deletes a large portion of the coding sequence, generating a null allele. The second mutation introduces a missense mutation (C282Y) into theHfe locus, but otherwise leaves the gene intact. This mutation is identical to the disease-causing mutation in patients with hereditary hemochromatosis. Mice carrying each of the two mutations were bred and analyzed. Homozygosity for either mutation results in postnatal iron loading. The effects of the null mutation are more severe than the effects of the C282Y mutation. Mice heterozygous for either mutation accumulate more iron than normal controls. Interestingly, although liver iron stores are greatly increased, splenic iron is decreased. We conclude that the C282Y mutation does not result in a null allele.	10.1038/35042073	Mice lacking HFE have more severe iron loading than mice carrying the mutation found in human patients with haemochromatosis.
10.1073/pnas.95.5.2492	103,243,553	Hereditary hemochromatosis (HH) is a common autosomal recessive disease characterized by increased iron absorption and progressive iron storage that results in damage to major organs in the body. Recently, a candidate gene for HH called HFE encoding a major histocompatibility complex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, we studied the effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates (96 ± 5% vs. 77 ± 3%, P < 0.007), and hepatic iron concentration was 8-fold higher than that of wild-type littermates (2,071 ± 450 vs. 255 ± 23 μg/g dry wt, P < 0.002). Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. This study shows that the HFE protein is involved in the regulation of iron homeostasis and that mutations in this gene are responsible for HH. The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload.	10.1038/35042073	Hfe knockout mice have iron overload, similar to human patients with haemochromatosis.
10.1073/pnas.96.19.10812	29,175,326	Aceruloplasminemia is an autosomal recessive disorder of iron metabolism. Affected individuals evidence iron accumulation in tissue parenchyma in association with absent serum ceruloplasmin. Genetic studies of such patients reveal inherited mutations in the ceruloplasmin gene. To elucidate the role of ceruloplasmin in iron homeostasis, we created an animal model of aceruloplasminemia by disrupting the murine ceruloplasmin ( Cp ) gene. Although normal at birth, Cp −/− mice demonstrate progressive accumulation of iron such that by one year of age all animals have a prominent elevation in serum ferritin and a 3- to 6-fold increase in the iron content of the liver and spleen. Histological analysis of affected tissues in these mice shows abundant iron stores within reticuloendothelial cells and hepatocytes. Ferrokinetic studies in Cp +/+ and Cp −/− mice reveal equivalent rates of iron absorption and plasma iron turnover, suggesting that iron accumulation results from altered compartmentalization within the iron cycle. Consistent with this concept, Cp −/− mice showed no abnormalities in cellular iron uptake but a striking impairment in the movement of iron out of reticuloendothelial cells and hepatocytes. Our findings reveal an essential physiologic role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores.	10.1038/35042073	This targeted disruption produced a mouse model for aceruloplasminaemia, and showed that ceruloplasmin is important for iron efflux from cells.
10.1126/science.8511591	125,130,042	Mammalian apolipoprotein B (apo B) exists in two forms, each the product of a single gene. The shorter form, apo B48, arises by posttranscriptional RNA editing whereby cytidine deamination produces a UAA termination codon. A full-length complementary DNA clone encoding an apo B messenger RNA editing protein (REPR) was isolated from rat small intestine. The 229-residue protein contains consensus phosphorylation sites and leucine zipper domains. HepG2 cell extracts acquire editing activity when mixed with REPR from oocyte extracts. REPR is essential for apo B messenger RNA editing, and the isolation and characterization of REPR may lead to the identification of other eukaryotic RNA editing proteins.	10.1038/35098584	This study describes the cloning of APOBEC1 , the first editing enzyme to be cloned.
10.1101/gad.11.3.321	40,547,896	Transgene expression of the apolipoprotein B mRNA-editing enzyme (APOBEC-1) causes dysplasia and carcinoma in mouse and rabbit livers. Using a modified differential display technique, we identified a novel mRNA (NAT1 for novel APOBEC-1 target no. 1) that is extensively edited at multiple sites in these livers. The aberrant editing alters encoded amino acids, creates stop codons, and results in markedly reduced levels of the NAT1 protein in transgenic mouse livers. NAT1 is expressed ubiquitously and is extraordinarily conserved among species. It has homology to the carboxy-terminal portion of the eukaryotic translation initiation factor (eIF) 4G that binds eIF4A and eIF4E to form eIF4F. NAT1 binds eIF4A but not eIF4E and inhibits both cap-dependent and cap-independent translation. NAT1 is likely to be a fundamental translational repressor, and its aberrant editing could contribute to the potent oncogenesis induced by overexpression of APOBEC-1.	10.1038/35098584	This study identifies NAT1 , the mRNA of which is extensively edited when APOBEC1 is overexpressed in mice and rabbits.
10.1073/pnas.250426397	104,013,517	We have identified three C/D-box small nucleolar RNAs (snoRNAs) and one H/ACA-box snoRNA in mouse and human. In mice, all four snoRNAs (MBII-13, MBII-52, MBII-85, and MBI-36) are exclusively expressed in the brain, unlike all other known snoRNAs. Two of the human RNA orthologues (HBII-52 and HBI-36) share this expression pattern, and the remainder, HBII-13 and HBII-85, are prevalently expressed in that tissue. In mice and humans, the brain-specific H/ACA box snoRNA (MBI-36 and HBI-36, respectively) is intron-encoded in the brain-specific serotonin 2C receptor gene. The three human C/D box snoRNAs map to chromosome 15q11–q13, within a region implicated in the Prader–Willi syndrome (PWS), which is a neurogenetic disease resulting from a deficiency of paternal gene expression. Unlike other C/D box snoRNAs, two snoRNAs, HBII-52 and HBII-85, are encoded in a tandemly repeated array of 47 or 24 units, respectively. In mouse the homologue of HBII-52 is processed from intronic portions of the tandem repeats. Interestingly, these snoRNAs were absent from the cortex of a patient with PWS and from a PWS mouse model, demonstrating their paternal imprinting status and pointing to their potential role in the etiology of PWS. Despite displaying hallmarks of the two families of ubiquitous snoRNAs that guide 2′-O-ribose methylation and pseudouridylation of rRNA, respectively, they lack any telltale rRNA complementarity. Instead, brain-specific C/D box snoRNA HBII-52 has an 18-nt phylogenetically conserved complementarity to a critical segment of serotonin 2C receptor mRNA, pointing to a potential role in the processing of this mRNA.	10.1038/35098584	Indicates a possible link between snoRNP-mediated modification of mRNA and ADAR activity.
10.1126/science.273.5280.1399	45,524,415	Amnesic patients and nondemented patients with Parkinson's disease were given a probabilistic classification task in which they learned which of two outcomes would occur on each trial, given the particular combination of cues that appeared. Amnesic patients exhibited normal learning of the task but had severely impaired declarative memory for the training episode. In contrast, patients with Parkinson's disease failed to learn the probabilistic classification task, despite having intact memory for the training episode. This double dissociation shows that the limbic-diencephalic regions damaged in amnesia and the neostriatum damaged in Parkinson's disease support separate and parallel learning systems. In humans, the neostriatum (caudate nucleus and putamen) is essential for the gradual, incremental learning of associations that is characteristic of habit learning. The neostriatum is important not just for motor behavior and motor learning but also for acquiring nonmotor dispositions and tendencies that depend on new associations.	10.1038/35036213	This study elegantly dissociates the role of the neostriatal system in mediating the acquisition of habitual responses to complex stimuli and that of the hippocampal system in mediating declarative memory.
10.1126/science.7652558	19,270,654	A patient with selective bilateral damage to the amygdala did not acquire conditioned autonomic responses to visual or auditory stimuli but did acquire the declarative facts about which visual or auditory stimuli were paired with the unconditioned stimulus. By contrast, a patient with selective bilateral damage to the hippocampus failed to acquire the facts but did acquire the conditioning. Finally, a patient with bilateral damage to both amygdala and hippocampal formation acquired neither the conditioning nor the facts. These findings demonstrate a double dissociation of conditioning and declarative knowledge relative to the human amygdala and hippocampus.	10.1038/35036213	A set of case studies show the separation of memory systems in humans, one involving mediation of fear conditioning by the amygdala and another involving mediation of declarative memory by the hippocampus.
10.1146/annurev.neuro.23.1.473	104,054,918	Associative learning enables animals to anticipate the occurrence of important outcomes. Learning occurs when the actual outcome differs from the predicted outcome, resulting in a prediction error. Neurons in several brain structures appear to code prediction errors in relation to rewards, punishments, external stimuli, and behavioral reactions. In one form, dopamine neurons, norepinephrine neurons, and nucleus basalis neurons broadcast prediction errors as global reinforcement or teaching signals to large postsynaptic structures. In other cases, error signals are coded by selected neurons in the cerebellum, superior colliculus, frontal eye fields, parietal cortex, striatum, and visual system, where they influence specific subgroups of neurons. Prediction errors can be used in postsynaptic structures for the immediate selection of behavior or for synaptic changes underlying behavioral learning. The coding of prediction errors may represent a basic mode of brain function that may also contribute to the processing of sensory information and the short-term control of behavior.	10.1038/35036228	A review of evidence that dopamine neurons provide a ‘prediction error’ signal that can orchestrate learning of the means to acquire rewards.
10.1101/gad.9.11.1316	18,716,084	Spore formation in Bacillus subtilis begins with an asymmetric cell division that superficially resembles the division of vegetative cells. Mutations in the spoIIIE gene of B. subtilis partially block partitioning of one chromosome into the smaller (prespore) compartment of the sporulating cell. Point mutations that specifically block prespore chromosome partitioning affect a carboxy-terminal domain of SpoIIIE that shows significant sequence similarity to the DNA transfer (Tra) proteins of several conjugative plasmids of Streptomyces. In wild-type sporulating cells, the prespore chromosome passes through an intermediate stage resembling the state in which spoIIIE mutant cells are blocked. The prespore chromosome is then transferred progressively through the newly formed spore septum. We propose that translocation of the prespore chromosome occurs by a mechanism that is functionally related to the conjugative transfer of plasmid DNA.	10.1038/35080005	References 1 and 2 report the discovery of the chromosome segregation function of SpoIIIE.
10.1126/science.290.5493.995	106,963,526	The SpoIIIE protein of Bacillus subtilis is required for chromosome segregation during spore formation. The COOH-terminal cytoplasmic part of SpoIIIE was shown to be a DNA-dependent adenosine triphosphatase (ATPase) capable of tracking along DNA in the presence of ATP, and the NH 2 -terminal part of the protein was found to mediate its localization to the division septum. Thus, during sporulation, SpoIIIE appears to act as a DNA pump that actively moves one of the replicated pair of chromosomes into the prespore. The presence of SpoIIIE homologs in a broad range of bacteria suggests that this mechanism for active transport of DNA may be widespread.	10.1038/35080005	Demonstration of DNA tracking by the SpoIIIE protein in vitro
10.1073/pnas.92.19.8630	97,477,230	Mutations in the spoIIIE gene prevent proper partitioning of one chromosome into the developing prespore during sporulation but have no overt effect on partitioning in vegetatively dividing cells. However, the expression of spoIIIE in vegetative cells and the occurrence of genes closely related to spoIIIE in a range of nonsporulating eubacteria suggested a more general function for the protein. Here we show that SpoIIIE protein is needed for optimal chromosome partitioning in vegetative cells of Bacillus subtilis when the normal tight coordination between septation and nucleoid partitioning is perturbed or when septum positioning is altered. A functional SpoIIIE protein allows cells to recover from a state in which their chromosome has been trapped by a closing septum. By analogy to its function during sporulation, we suggest that SpoIIIE facilitates partitioning by actively translocating the chromosome out of the septum. In addition to enhancing the fidelity of nucleoid partitioning, SpoIIIE also seems to be required for maximal resistance to antibiotics that interfere with DNA metabolism. The results have important implications for our understanding of the functions of genes involved in the primary partitioning machinery in bacteria and of how septum placement is controlled.	10.1038/35080005	Demonstration that SpoIIIE has a general role in chromosome segregation.
10.1073/pnas.96.25.14553	123,934,314	Shortly after the synthesis of the two cells required for sporulation in Bacillus subtilis , the membranes of the larger mother cell begin to migrate around and engulf the smaller forespore cell. At the completion of this process the leading edges of the migrating membrane meet and fuse, releasing the forespore into the mother cell cytoplasm. We developed a fluorescent membrane stain-based assay for this membrane fusion event, and we isolated mutants defective in the final stages of engulfment or membrane fusion. All had defects in spoIIIE, which is required for translocation of the forespore chromosome across the polar septum. We isolated one spoIIIE mutant severely defective in chromosome translocation, but not in membrane fusion; this mutation disrupts the ATP/GTP-binding site of SpoIIIE, suggesting that ATP binding and hydrolysis are required for DNA translocation but not for the late engulfment function of SpoIIIE. We also correlated relocalization of SpoIIIE-green fluorescent protein from the sporulation septum to the forespore pole with the completion of membrane fusion and engulfment. We suggest that SpoIIIE is required for the final steps of engulfment and that it may regulate or catalyze membrane fusion events.	10.1038/35080005	Demonstration of the membrane fusion function of SpoIIIE protein during sporulation.
10.1046/j.1365-2958.1999.01198.x	109,139,827	Chromosome dimers, formed by homologous recombination between sister chromosomes, normally require cell division to be resolved into monomers by site‐specific recombination at the dif locus of Escherichia coli . We report here that it is not in fact cell division per se that is required for dimer resolution but the action of the cytoplasmic domain of FtsK, which is a bifunctional protein required both for cell division and for chromosome partition.	10.1038/35080005	Unexpected finding of a role for FtsK in the resolution of chromosome dimers.
10.1126/science.282.5392.1321	38,582,068	Glycine receptors are anchored at inhibitory chemical synapses by a cytoplasmic protein, gephyrin. Molecular cloning revealed the similarity of gephyrin to prokaryotic and invertebrate proteins essential for synthesizing a cofactor required for activity of molybdoenzymes. Gene targeting in mice showed that gephyrin is required both for synaptic clustering of glycine receptors in spinal cord and for molybdoenzyme activity in nonneural tissues. The mutant phenotype resembled that of humans with hereditary molybdenum cofactor deficiency and hyperekplexia (a failure of inhibitory neurotransmission), suggesting that gephyrin function may be impaired in both diseases.	10.1038/35067500	Production of a gephryin knockout mouse. The phenotype is lethal and the mouse shows an exaggerated startle response and loss of glycine receptor clustering. In addition, there are gross metabolic deficits in agreement with a role for gephyrin in the production of the Moco cofactor essential for the function of molybdenum-containing enzymes.
10.1073/pnas.97.15.8594	58,561,111	γ-Aminobutyric acid type A receptors (GABA A Rs) are ligand-gated chloride channels that exist in numerous distinct subunit combinations. At postsynaptic membrane specializations, different GABA A R isoforms colocalize with the tubulin-binding protein gephyrin. However, direct interactions of GABA A R subunits with gephyrin have not been reported. Recently, the GABA A R-associated protein GABARAP was found to bind to the γ2 subunit of GABA A Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Confocal analysis of neurons derived from wild-type and gephyrin-knockout mice revealed that GABARAP is highly enriched in intracellular compartments, but not at gephyrin-positive postsynaptic membrane specializations. Our data indicate that GABARAP–gephyrin interactions are not important for postsynaptic GABA A R anchoring but may be implicated in receptor sorting and/or targeting mechanisms. Consistent with this idea, a close homolog of GABARAP, p16, has been found to function as a late-acting intra-Golgi transport factor.	10.1038/35067500	The distribution and interaction of GABA A -receptor-associated protein (GABARAP) and gephyrin were compared in cultured neurons. GABARAP was found almost exclusively in intracellular compartments compared with synaptic sites where a much greater abundance of gephyrin was demonstrated. This distribution is consistent with a role for GABARAP in GABA A receptor transport rather than synaptic anchoring.
10.1091/mbc.1.1.99	16,859,572	A rapid rise in the level of cytosolic free calcium ([Ca2+]i) is believed to be one of several early triggering signals in the activation of T lymphocytes by antigen. Although Ca2+ release from intracellular stores and its contribution to Ca2+ signaling in many cell types is well documented, relatively little is known regarding the role and mechanism of Ca2+ entry across the plasma membrane. We have investigated mitogen-triggered Ca2+ signaling in individual cells of the human T-leukemia-derived line, Jurkat, using fura-2 imaging and patch-clamp recording techniques. Phytohemagglutinin (PHA), a mitogenic lectin, induces repetitive [Ca2+]i oscillations in these cells peaking at micromolar levels with a period of 90-120 s. The oscillations depend critically upon Ca2+ influx across the plasma membrane, as they are rapidly terminated by removal of extracellular Ca2+, addition of Ca(2+)-channel blockers such as Ni2+ or Cd2+, or membrane depolarization. Whole-cell and perforated-patch recording methods were combined with fura-2 measurements to identify the mitogen-activated Ca2+ conductance involved in this response. A small, highly selective Ca2+ conductance becomes activated spontaneously in whole-cell recordings and in response to PHA in perforated-patch experiments. This conductance has properties consistent with a role in T-cell activation, including activation by PHA, lack of voltage-dependent gating, inhibition by Ni2+ or Cd2+, and regulation by intracellular Ca2+. Moreover, a tight temporal correlation between oscillations of Ca2+ conductance and [Ca2+]i suggests a role for the membrane Ca2+ conductance in generating [Ca2+]i oscillations in activated T cells.	10.1038/35077544	Lewis and Cahalan described a small highly selective Ca 2+ conductance in lymphocytes that was activated by low intracellular calcium. This current was subsequently named I CRAC by Hoth and Penner (reference 13
10.1083/jcb.138.6.1333	16,988,377	TRPC3 (or Htrp3) is a human member of the trp family of Ca2+-permeable cation channels. Since expression of TRPC3 cDNA results in markedly enhanced Ca2+ influx in response to stimulation of membrane receptors linked to phospholipase C (Zhu, X., J. Meisheng, M. Peyton, G. Bouley, R. Hurst, E. Stefani, and L. Birnbaumer. 1996. Cell. 85:661–671), we tested whether TRPC3 might represent a Ca2+ entry pathway activated as a consequence of depletion of intracellular calcium stores. CHO cells expressing TRPC3 after intranuclear injection of cDNA coding for TRPC3 were identified by fluorescence from green fluorescent protein. Expression of TRPC3 produced cation currents with little selectivity for Ca2+ over Na+. These currents were constitutively active, not enhanced by depletion of calcium stores with inositol-1,4,5-trisphosphate or thapsigargin, and attenuated by strong intracellular Ca2+ buffering. Ionomycin led to profound increases of currents, but this effect was strictly dependent on the presence of extracellular Ca2+. Likewise, infusion of Ca2+ into cell through the patch pipette increased TRPC3 currents. Therefore, TRPC3 is stimulated by a Ca2+-dependent mechanism. Studies on TRPC3 in inside-out patches showed cation-selective channels with 60-pS conductance and short (&lt;2 ms) mean open times. Application of ionomycin to cells increased channel activity in cell-attached patches. Increasing the Ca2+ concentration on the cytosolic side of inside-out patches (from 0 to 1 and 30 μM), however, failed to stimulate channel activity, even in the presence of calmodulin (0.2 μM). We conclude that TRPC3 codes for a Ca2+-permeable channel that supports Ca2+-induced Ca2+-entry but should not be considered store operated.	10.1038/35077544	Presented the first unequivocal evidence that TRPCs form functional ion channels and challenged the concept of TRPCs being store-operated by showing that TRPC3 is activated by intracellular Ca 2+ but not by store depletion.
10.1126/science.1058519	62,416,831	We cloned and characterized a protein kinase and ion channel, TRP-PLIK. As part of the long transient receptor potential channel subfamily implicated in control of cell division, it is a protein that is both an ion channel and a protein kinase. TRP-PLIK phosphorylated itself, displayed a wide tissue distribution, and, when expressed in CHO-K1 cells, constituted a nonselective, calcium-permeant, 105-picosiemen, steeply outwardly rectifying conductance. The zinc finger containing α-kinase domain was functional. Inactivation of the kinase activity by site-directed mutagenesis and the channel's dependence on intracellular adenosine triphosphate (ATP) demonstrated that the channel's kinase activity is essential for channel function.	10.1038/35077544	Characterizes the ion channel and kinase properties of the novel protein TRP-PLIK, showing that the kinase activity of the protein is required for proper channel function. It is also the first electrophysiological study of a member of the TRPM subgroup.
10.1083/jcb.149.1.33	29,344,487	Monitoring the fusion of constitutive traffic with the plasma membrane has remained largely elusive. Ideally, fusion would be monitored with high spatial and temporal resolution. Recently, total internal reflection (TIR) microscopy was used to study regulated exocytosis of fluorescently labeled chromaffin granules. In this technique, only the bottom cellular surface is illuminated by an exponentially decaying evanescent wave of light. We have used a prism type TIR setup with a penetration depth of ∼50 nm to monitor constitutive fusion of vesicular stomatitis virus glycoprotein tagged with the yellow fluorescent protein. Fusion of single transport containers (TCs) was clearly observed and gave a distinct analytical signature. TCs approached the membrane, appeared to dock, and later rapidly fuse, releasing a bright fluorescent cloud into the membrane. Observation and analysis provided insight about their dynamics, kinetics, and position before and during fusion. Combining TIR and wide-field microscopy allowed us to follow constitutive cargo from the Golgi complex to the cell surface. Our observations include the following: (1) local restrained movement of TCs near the membrane before fusion; (2) apparent anchoring near the cell surface; (3) heterogeneously sized TCs fused either completely; or (4) occasionally larger tubular-vesicular TCs partially fused at their tips.	10.1038/35067069	References 26 and 27 image for the first time the exocytosis of constitutive secretory vesicles.
10.1146/annurev.psych.49.1.447	18,160,828	▪ Abstract For many decades, research in judgment and decision making has examined behavioral violations of rational choice theory. In that framework, rationality is expressed as a single correct decision shared by experimenters and subjects that satisfies internal coherence within a set of preferences and beliefs. Outside of psychology, social scientists are now debating the need to modify rational choice theory with behavioral assumptions. Within psychology, researchers are debating assumptions about errors for many different definitions of rationality. Alternative frameworks are being proposed. These frameworks view decisions as more reasonable and adaptive than previously thought. For example, “rule following.” Rule following, which occurs when a rule or norm is applied to a situation, often minimizes effort and provides satisfying solutions that are “good enough,” though not necessarily the best. When rules are ambiguous, people look for reasons to guide their decisions. They may also let their emotions take charge. This chapter presents recent research on judgment and decision making from traditional and alternative frameworks.	10.1038/35049054	A balanced survey of the current psychological perspective on deciding.
10.1146/annurev.neuro.21.1.227	61,329,572	▪ Abstract The newly defined field of cognitive neuroscience attempts to draw together the study of all brain mechanisms that underlie our mental life. Historically, the major sensory pathways have provided the most trustworthy insights into how the brain supports cognitive functions such as perception, attention, and short-term memory. The links between neural activity and perception, in particular, have been studied revealingly in recent decades. Here we review the striking progress in this area, giving particular emphasis to the kinds of neural events that underlie the perceptual judgments of conscious observers.	10.1038/35049054	A comprehensive and enlightening review of the neural processes in the cerebral cortex that underlie sensation and perception.
10.1152/jn.1996.76.6.4040	122,073,315	1. The latency between the appearance of a popout search display and the eye movement to the oddball target of the display varies from trial to trial in both humans and monkeys. The source of the delay and variability of reaction time is unknown but has been attributed to as yet poorly defined decision processes. 2. We recorded neural activity in the frontal eye field (FEF), an area regarded as playing a central role in producing purposeful eye movements, of monkeys (Macaca mulatta) performing a popout visual search task. Eighty-four neurons with visually evoked activity were analyzed. Twelve of these neurons had a phasic response associated with the presentation of the visual stimulus. The remaining neurons had more tonic responses that persisted through the saccade. Many of the neurons with more tonic responses resembled visuomovement cells in that they had activity that increased before a saccade into their response field. 3. The visual response latencies of FEF neurons were determined with the use of a Poisson spike train analysis. The mean visual latency was 67 ms (minimum = 35 ms, maximum = 138 ms). The visual response latencies to the target presented alone, to the target presented with distractors, or to the distractors did not differ significantly. 4. The initial visual activation of FEF neurons does not discriminate the target from the distractors of a popout visual search stimulus array, but the activity evolves to a state that discriminates whether the target of the search display is within the receptive field. We tested the hypothesis that the source of variability of saccade latency is the time taken by neurons involved in saccade programming to select the target for the gaze shift. 5. With the use of an analysis adapted from signal detection theory, we determined when the activity of single FEF neurons can reliably indicate whether the target or distractors are present within their response fields. The time of target discrimination partitions the reaction time into a perceptual stage in which target discrimination takes place, and a motor stage in which saccade programming and generation take place. The time of target discrimination occurred most often between 120 and 150 ms after stimulus presentation. 6. We analyzed the time course of target discrimination in the activity of single cells after separating trials into short, medium, and long saccade latency groups. Saccade latency was not correlated with the duration of the perceptual stage but was correlated with the duration of the motor stage. This result is inconsistent with the hypothesis that the time taken for target discrimination, as indexed by FEF neurons, accounts for the wide variability in the time of movement initiation. 7. We conclude that the variability observed in saccade latencies during a simple visual search task is largely due to postperceptual motor processing following target discrimination. Signatures of both perceptual and postperceptual processing are evident in FEF. Procrastination in the output stage may prevent stereotypical behavior that would be maladaptive in a changing environment.	10.1038/35049054	This paper describes the time course of the neural process of discriminating the target in a visual search array. It is the first to relate the time of target selection to the time of saccade initiation.
10.1523/jneurosci.11-06-01855.1991	79,675,926	It has been proposed that the premotor cortex plays a role in the selection of motor programs based on environmental context. To test this hypothesis, we recorded the activity of single neurons as monkeys learned visuomotor associations. The hypothesis predicts that task- related premotor cortical activity before learning should differ from that afterward. We found that a substantial population of premotor cortex neurons, over half of those adequately tested, showed the predicted learning-dependent changes in activity. The present findings support a role for premotor cortex in motor preparation, generally, and suggest a specific role in the selection of movements on the basis of arbitrary associations.	10.1038/35049054	A demonstration of how the premotor cortex is involved in learning arbitrary associations of stimulus to response.
10.1017/s095252380000715x	61,653,361	Abstract We have previously documented the exquisite motion sensitivity of neurons in extrastriate area MT by studying the relationship between their responses and the direction and strength of visual motion signals delivered to their receptive fields. These results suggested that MT neurons might provide the signals supporting behavioral choice in visual discrimination tasks. To approach this question from another direction, we have now studied the relationship between the discharge of MT neurons and behavioral choice, independently of the effects of visual stimulation. We found that trial-to-trial variability in neuronal signals was correlated with the choices the monkey made. Therefore, when a directionally selective neuron in area MT fires more vigorously, the monkey is more likely to make a decision in favor of the preferred direction of the cell. The magnitude of the relationship was modest, on average, but was highly significant across a sample of 299 cells from four monkeys. The relationship was present for all stimuli (including those without a net motion signal), and for all but the weakest responses. The relationship was reduced or eliminated when the demands of the task were changed so that the directional signal carried by the cell was less informative. The relationship was evident within 50 ms of response onset, and persisted throughout the stimulus presentation. On average, neurons that were more sensitive to weak motion signals had a stronger relationship to behavior than those that were less sensitive. These observations are consistent with the idea that neuronal signals in MT are used by the monkey to determine the direction of stimulus motion. The modest relationship between behavioral choice and the discharge of any one neuron, and the prevalence of the relationship across the population, make it likely that signals from many neurons are pooled to form the data on which behavioral choices are based.	10.1038/35049054	This paper describes in quantitative terms the relationship between neural activity and the perceptual report when the discriminative stimulus is weak or absent. Even when no sensory evidence was provided, a weak correlation was observed between the report of the monkeys and the discharge rate of the neurons in area MT of the extrastriate visual cortex.
10.1073/pnas.120018597	122,095,250	Monkeys are able to discriminate the difference in frequency between two periodic mechanical vibrations applied sequentially to the fingertips. It has been proposed that this ability is mediated by the periodicity of the responses in the quickly adapting (QA) neurons of the primary somatosensory cortex (S1), instead of the average firing rates. We recorded from QA neurons of S1 while monkeys performed the vibrotactile discrimination task. We found that the periodic mechanical vibrations can be represented both in the periodicity and in the firing rate responses to varying degrees across the QA neuronal population. We then computed neurometric functions by using both the periodicity and the firing rate and sought to determine which of these two measures is associated with the psychophysical performance. We found that neurometric thresholds based on the firing rate are very similar to the animal's psychometric thresholds whereas neurometric thresholds based on periodicity are far lower than those thresholds. These results indicate that an observer could solve this task with a precision similar to that of the monkey, based only on the firing rate produced during the stimulus periods.	10.1038/35049054	This paper shows the quantitative relationship between the firing rate of neurons in somatosensory cortex and a monkey's report of the frequency of mechanical vibrations applied to the fingertips. The somatosensory cortex, like the visual system, produces decisions that are based on the activity of just a few neurons.
10.1126/science.2772635	16,676,625	Neuronal activity in the superior temporal sulcus of monkeys, a cortical region that plays an important role in analyzing visual motion, was related to the subjective perception of movement during a visual task. Single neurons were recorded while monkeys ( Macaca mulatta ) discriminated the direction of motion of stimuli that could be seen moving in either of two directions during binocular rivalry. The activity of many neurons was dictated by the retinal stimulus. Other neurons, however, reflected the monkeys' reported perception of motion direction, indicating that these neurons in the superior temporal sulcus may mediate the perceptual experience of a moving object.	10.1038/35049054	Binocular rivalry with moving gratings was used to create an ambiguous stimulus that could support two distinct perceptual states. The activity of some neurons in area MT was associated with the perceptual report and not the retinal stimulation. This is the first paper to report an explicit association between the activity of neurons in the visual system and the perceptual state of monkeys.
10.1523/jneurosci.12-06-02331.1992	80,128,592	Physiological and behavioral evidence suggests that the activity of direction selective neurons in visual cortex underlies the perception of moving visual stimuli. We tested this hypothesis by measuring the effects of cortical microstimulation on perceptual judgements of motion direction. To accomplish this, rhesus monkeys were trained to discriminate the direction of motion in a near-threshold, stochastic motion display. For each experiment, we positioned a microelectrode in the middle of a cluster of neurons that shared a common preferred direction of motion. The psychophysical task was then adjusted so that the visual display was presented directly over the neurons' receptive field. The monkeys were required to discriminate between motion shown either in the direction preferred by the neurons or in the opposite direction. On half the trials of an experiment, we applied electrical microstimulation while monkeys viewed the motion display. We hypothesized that enhancing the neurons' discharge rate would introduce a directionally specific signal into the cortex and thereby influence the monkeys' choices on the discrimination task. We compared the monkeys' performance on “stimulated” and “nonstimulated” trials in 139 experiments; all trials within an experiment were presented in random order. Statistically significant effects of microstimulation were obtained in 89 experiments. In 86 of the 89 experiments with significant effects (97%), the monkeys indicated that motion was in the neurons' preferred direction more frequently on stimulated trials than on nonstimulated trials. The data demonstrate a functional link between the activity of direction selective neurons and perceptual judgements of motion direction.	10.1038/35049054	This paper shows that electrical stimulation of area MT influences monkeys' decisions about the direction of motion in a display.
10.1126/science.282.5392.1335	103,660,470	Most natural actions are chosen voluntarily from many possible choices. An action is often chosen based on the reward that it is expected to produce. What kind of cellular activity in which area of the cerebral cortex is involved in selecting an action according to the expected reward value? Results of an analysis in monkeys of cellular activity during the performance of reward-based motor selection and the effects of chemical inactivation are presented. We suggest that cells in the rostral cingulate motor area, one of the higher order motor areas in the cortex, play a part in processing the reward information for motor selection.	10.1038/35049054	Monkeys were required to change their behaviour to continue obtaining reinforcement. The cue to change behaviours was a change in the reinforcement. Neurons in anterior cingulate cortex signalled the transitions.
10.1126/science.275.5306.1593	41,713,287	The capacity to predict future events permits a creature to detect, model, and manipulate the causal structure of its interactions with its environment. Behavioral experiments suggest that learning is driven by changes in the expectations about future salient events such as rewards and punishments. Physiological work has recently complemented these studies by identifying dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events. Taken together, these findings can be understood through quantitative theories of adaptive optimizing control.	10.1038/35049054	This paper proposes a mechanistic model for how behaviour is shaped by reinforcement contingencies.
10.1126/science.274.5286.427	38,402,700	When humans respond to sensory stimulation, their reaction times tend to be long and variable relative to neural transduction and transmission times. The neural processes responsible for the duration and variability of reaction times are not understood. Single-cell recordings in a motor area of the cerebral cortex in behaving rhesus monkeys ( Macaca mulatta ) were used to evaluate two alternative mathematical models of the processes that underlie reaction times. Movements were initiated if and only if the neural activity reached a specific and constant threshold activation level. Stochastic variability in the rate at which neural activity grew toward that threshold resulted in the distribution of reaction times. This finding elucidates a specific link between motor behavior and activation of neurons in the cerebral cortex.	10.1038/35049054	This paper provides neurophysiological evidence contradicting one model and supporting an alternative model of response time. Movement-related neural activity in the frontal eye field corresponds to a race or diffusion with a variable rate to a fixed threshold.
10.1111/j.1467-9280.1993.tb00586.x	38,401,783	Humans can monitor actions and compensate for errors. Analysis of the human event-related brain potentials (ERPs) accompanying errors provides evidence for a neural process whose activity is specifically associated with monitoring and compensating for erroneous behavior. This error-related activity is enhanced when subjects strive for accurate performance but is diminished when response speed is emphasized at the expense of accuracy. The activity is also related to attempts to compensate for the erroneous behavior.	10.1038/35049054	This paper describes the error-related negativity, a scalp potential that appears when human subjects make errors. The brain's ability to detect errors is a prerequisite to exerting executive control over behaviour.
10.1126/science.274.5293.1724	41,544,908	Neurons in the cortex of behaving animals show temporally irregular spiking patterns. The origin of this irregularity and its implications for neural processing are unknown. The hypothesis that the temporal variability in the firing of a neuron results from an approximate balance between its excitatory and inhibitory inputs was investigated theoretically. Such a balance emerges naturally in large networks of excitatory and inhibitory neuronal populations that are sparsely connected by relatively strong synapses. The resulting state is characterized by strongly chaotic dynamics, even when the external inputs to the network are constant in time. Such a network exhibits a linear response, despite the highly nonlinear dynamics of single neurons, and reacts to changing external stimuli on time scales much smaller than the integration time constant of a single neuron.	10.1038/35049054	The well-known irregularity of neural activity can arise from the deterministic but unpredictable dynamics of neural networks.
10.1126/science.279.5350.509	41,692,574	The actin cytoskeleton mediates a variety of essential biological functions in all eukaryotic cells. In addition to providing a structural framework around which cell shape and polarity are defined, its dynamic properties provide the driving force for cells to move and to divide. Understanding the biochemical mechanisms that control the organization of actin is thus a major goal of contemporary cell biology, with implications for health and disease. Members of the Rho family of small guanosine triphosphatases have emerged as key regulators of the actin cytoskeleton, and furthermore, through their interaction with multiple target proteins, they ensure coordinated control of other cellular activities such as gene transcription and adhesion.	10.1038/35103068	These reviews (References 18 20 and 21 ) summarize how the Rho-family GTPases regulate various cellular processes, such as cytoskeletal dynamics, cell adhesion and gene transcription.
10.1242/jcs.114.10.1829	104,363,176	Rac1, a member of the Ρ family small GTPases, regulates E-cadherin-mediated cell-cell adhesion. However, it remains to be clarified how the localization and activation of Rac1 are regulated at sites of cell-cell contact. Here, using enhanced green fluorescence protein (EGFP)-tagged Rac1, we demonstrate that EGFP-Rac1 is colocalized with E-cadherin at sites of cell-cell contact and translocates to the cytosol during disruption of E-cadherin-mediated cell-cell adhesion by Ca(2+) chelation. Re-establishment of cell-cell adhesion by restoration of Ca(2)(+) caused EGFP-Rac1 to become relocalized, together with E-cadherin, at sites of cell-cell contact. Engagement of E-cadherin to the apical membrane by anti-E-cadherin antibody (ECCD-2) recruited EGFP-Rac1. We also investigated whether E-cadherin-mediated cell-cell adhesion induced Rac1 activation by measuring the amounts of GTP-bound Rac1 based on its specific binding to the Cdc42/Rac1 interactive binding region of p21-activated kinase. The formation of E-cadherin-mediated cell-cell adhesion induced Rac1 activation. This activation was inhibited by treatment of cells with a neutralizing antibody (DECMA-1) against E-cadherin, or with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase). IQGAP1, an effector of Rac1, and EGFP-Rac1 behaved in a similar manner during the formation of E-cadherin-mediated cell-cell adhesion. Rac1 activation was also confirmed by measuring the amounts of coimmunoprecipitated Rac1 with IQGAP1 during the establishment of cell-cell adhesion. Taken together, these results suggest that Rac1 is recruited at sites of E-cadherin-mediated cell-cell adhesion and then activated, possibly through PI 3-kinase. http://www/biologists.com/JCS/movies/jcs2094.html	10.1038/35103068	References 27 66 and 71 show that E-cadherin-mediated cell?cell adhesion leads to the rapid activation of Rac1 or Cdc42.
10.1083/jcb.137.6.1421	104,233,584	Cadherins are calcium-dependent cell–cell adhesion molecules that require the interaction of the cytoplasmic tail with the actin cytoskeleton for adhesive activity. Because of the functional relationship between cadherin receptors and actin filament organization, we investigated whether members of the Rho family of small GTPases are necessary for cadherin adhesion. In fibroblasts, the Rho family members Rho and Rac regulate actin polymerization to produce stress fibers and lamellipodia, respectively. In epithelial cells, we demonstrate that Rho and Rac are required for the establishment of cadherin-mediated cell–cell adhesion and the actin reorganization necessary to stabilize the receptors at sites of intercellular junctions. Blocking endogenous Rho or Rac selectively removed cadherin complexes from junctions induced for up to 3 h, while desmosomes were not perturbed. In addition, withdrawal of cadherins from intercellular junctions temporally precedes the removal of CD44 and integrins, other microfilament-associated receptors. Our data showed that the concerted action of Rho and Rac modulate the establishment of cadherin adhesion: a constitutively active form of Rac was not sufficient to stabilize cadherindependent cell–cell contacts when endogenous Rho was inhibited. Upon induction of calcium-dependent intercellular adhesion, there was a rapid accumulation of actin at sites of cell–cell contacts, which was prevented by blocking cadherin function, Rho or Rac activity. However, if cadherin complexes are clustered by specific antibodies attached to beads, actin recruitment to the receptors was perturbed by inhibiting Rac but not Rho. Our results provide new insights into the role of the small GTPases in the cadherin-dependent cell– cell contact formation and the remodelling of actin filaments in epithelial cells.	10.1038/35103068	This paper first documented that the Rho-family GTPases, Rac1 and RhoA, are required for cadherin-mediated cell?cell adhesion in cultured cells.
10.1126/science.281.5378.832	17,651,828	The small guanosine triphosphatases (GTPases) Cdc42 and Rac1 regulate E-cadherin–mediated cell-cell adhesion. IQGAP1, a target of Cdc42 and Rac1, was localized with E-cadherin and β-catenin at sites of cell-cell contact in mouse L fibroblasts expressing E-cadherin (EL cells), and interacted with E-cadherin and β-catenin both in vivo and in vitro. IQGAP1 induced the dissociation of α-catenin from a cadherin-catenin complex in vitro and in vivo. Overexpression of IQGAP1 in EL cells, but not in L cells expressing an E-cadherin–α-catenin chimeric protein, resulted in a decrease in E-cadherin–mediated cell-cell adhesive activity. Thus, IQGAP1, acting downstream of Cdc42 and Rac1, appears to regulate cell-cell adhesion through the cadherin-catenin pathway.	10.1038/35103068	This paper showed for the first time how Rac1 and Cdc42 regulate E-cadherin-mediated cell?cell adhesion. IQGAP1, an effector of Rac1 and Cdc42, negatively regulates E-cadherin-mediated cell?cell adhesion through dissociation of α-catenin from the cadherin?catenin complex.
10.1242/jcs.114.4.695	62,664,750	The molecular basis for contact inhibition of cell locomotion is still largely unknown. Cadherins, the major receptors mediating cell-cell adhesion, associate in the cytoplasm with armadillo family proteins, including beta- and gamma-catenin and p120 catenin (p120ctn). E-cadherin-mediated contact formation was shown to inhibit cellular motility. We examine whether p120ctn may have a role in this regulation. We show here that overexpression of p120ctn in fibroblasts and epithelial cells induces pronounced changes in cell shape, motility and adhesion to the extracellular matrix. p120ctn-transfected cells display increased filopodial/lamellipodial activity, decreased contractility and focal adhesion formation, and augmented migratory ability. These effects of p120ctn are mediated by small GTPases of the Rho family. Direct assessment of the activity of these GTPases in cells expressing a 5-fold higher level of p120ctn as compared to non-transfected control cells revealed significant augmentation of Cdc42 and Rac activity. Moreover, co-transfection of p120ctn with dominant-negative Cdc42 and Rac, or constitutively active Rho suppressed morphological effects of p120ctn. Confocal immunofluorescence visualization of the distribution of endogenous p120ctn in dense cultures showed that formation of cadherin-mediated cell-cell contacts is accompanied by sequestering of p120ctn to the junction regions. In sparse cultures p120ctn is distributed over the cytoplasm. Co-transfection with an excess of E-cadherin leads to sequestration of exogenous p120ctn to cell-cell junctions or to small cadherin-containing vesicles, and abolishes p120ctn effects on cell morphology. Thus, p120ctn may couple the formation and disruption of cadherin-mediated contacts with regulation of cell motility by triggering pathway(s) affecting Rho family GTPases.	10.1038/35103068	A series of papers (references 76 77 and 78 ) show that p120ctn modulates the activity of the Rho-family GTPases, and that E-cadherin expression inhibits these actions.
10.1126/science.6356363	101,069,747	The promoter or regulatory region of the mouse gene for metallothionein-I was fused to the structural gene coding for human growth hormone. These fusion genes were introduced into mice by microinjection of fertilized eggs. Twenty-three (70 percent) of the mice that stably incorporated the fusion genes showed high concentrations of human growth hormone in their serum and grew significantly larger than control mice. Synthesis of human growth hormone was induced further by cadmium or zinc, which normally induce metallothionein gene expression. Transgenic mice that expressed human growth hormone also showed increased concentrations of insulin-like growth factor I in their serum. Histology of their pituitaries suggests dysfunction of the cells that normally synthesize growth hormone. The fusion genes were expressed in all tissues examined, but the ratio of human growth hormone messenger RNA to endogenous metallothionein-I messenger RNA varied among different tissues and different animals, suggesting that expression of the foreign genes is influenced by site of integration and tissue environment.	10.1038/35048058	A major advance in regulating the size of an animal.
10.1098/rstb.1952.0012	41,744,237	It is suggested that a system of chemical substances, called morphogens, reacting together and diffusing through a tissue, is adequate to account for the main phenomena of morphogenesis. Such a system, although it may originally be quite homogeneous, may later develop a pattern or structure due to an instability of the homogeneous equilibrium, which is triggered off by random disturbances. Such reaction-diffusion systems are considered in some detail in the case of an isolated ring of cells, a mathematically convenient, though biologically unusual system. The investigation is chiefly concerned with the onset of instability. It is found that there are six essentially different forms which this may take. In the most interesting form stationary waves appear on the ring. It is suggested that this might account, for instance, for the tentacle patterns on Hydra and for whorled leaves. A system of reactions and diffusion on a sphere is also considered. Such a system appears to account for gastrulation. Another reaction system in two dimensions gives rise to patterns reminiscent of dappling. It is also suggested that stationary waves in two dimensions could account for the phenomena of phyllotaxis. The purpose of this paper is to discuss a possible mechanism by which the genes of a zygote may determine the anatomical structure of the resulting organism. The theory does not make any new hypotheses; it merely suggests that certain well-known physical laws are sufficient to account for many of the facts. The full understanding of the paper requires a good knowledge of mathematics, some biology, and some elementary chemistry. Since readers cannot be expected to be experts in all of these subjects, a number of elementary facts are explained, which can be found in text-books, but whose omission would make the paper difficult reading.	10.1038/35048058	A tour de force of theoretical biology. Turing's genius, ability to explain things simply, and kind personality are evident in this paper.
10.1073/pnas.94.7.3363	100,819,460	In rats with unilateral lesions of the nigrostriatal dopamine pathway with 6-hydroxydopamine, the motor stimulating effects of levodopa, an indirect dopamine receptor agonist, evidenced by contraversive rotations, become enhanced upon repeated intermittent administration. However, the mechanisms of this behavioral sensitization are essentially unknown. We show that development of sensitization is accompanied by a progressive appearance of D 3 receptor mRNA and binding sites, visualized by in situ hybridization and 7-[ 3 H]hydroxy- N , N -di- n -propyl-2-aminotetralin autoradiography, respectively, occurring in the denervated caudate putamen, a brain area from which this receptor subtype is normally absent. Development and decay of these two processes occur with closely parallel time courses, whereas there were no marked changes in D 1 or D 2 receptor mRNAs. D 3 receptor induction by levodopa is mediated by repeated D 1 receptor stimulation, since it is prevented by the antagonist SCH 33390 and mimicked by the agonist SKF 38393, but not by two D 2 receptor agonists. The enhanced behavioral response to levodopa is mediated by the newly synthesized D 3 receptor, since it is antagonized by nafadotride, a preferential D 3 receptor antagonist, in low dosage, which has no such effect before D 3 receptor induction. D 3 receptor induction and behavioral sensitization are also accompanied by a sustained enhancement of prodynorphin mRNA level and a progressively decreasing expression of the preprotachykinin gene. We propose that imbalance between dynorphin and substance P release from the same striatonigral motor efferent pathway, related to D 3 receptor induction, is responsible for behavioral sensitization.	10.1038/35086062	Proof-of-principle study showing the crucial role of the ectopic expression of the dopamine D3 receptor in levodopa sensitization.
10.1126/science.270.5239.1189	122,963,455	The eye is a privileged site that cannot tolerate destructive inflammatory responses. Inflammatory cells entering the anterior chamber of the eye in response to viral infection underwent apoptosis that was dependent on Fas (CD95)-Fas ligand (FasL) and produced no tissue damage. In contrast, viral infection in gld mice, which lack functional FasL, resulted in an inflammation and invasion of ocular tissue without apoptosis. Fas-positive but not Fas-negative tumor cells were killed by apoptosis when placed within isolated anterior segments of the eyes of normal but not FasL-negative mice. FasL messenger RNA and protein were detectable in the eye. Thus, Fas-FasL interactions appear to be an important mechanism for the maintenance of immune privilege.	10.1038/35103104	This study shows for the first time that FasL is functionally and constitutively expressed in the eye ? an immune-privileged site.
10.4049/jimmunol.167.3.1338	68,474,674	Abstract Constitutive Fas ligand (FasL) expression by specialized cells in the body participates in the immune privilege status of tissues containing these cells. This property has been used to prevent rejection of allogeneic grafts. Nevertheless, the mechanism responsible for such protection has not been fully elucidated. Unfortunately, grafting of FasL transgenic (TG) tissues has been unsuccessful. We have generated TG mice expressing FasL (soluble + membrane bound) on thyroid follicular cells (TFC), and used them to show that ectopic FasL expression prevents thyroid allograft rejection. FasL expression on TFC led to markedly decreased anti-allogeneic, cytotoxic, and helper T lymphocyte activities. The alloantibody response in TG thyroid recipients was either completely inhibited or switched toward a T2-Ab response. Surprisingly, the beneficial effect of FasL on TG thyroid grafts was abolished by host CD4+ T cell depletion. Host CD8+ T cell depletion improved nontransgenic (NTG), but not TG graft survival. Altogether, our results suggest that FasL-induced tolerance is concomitant with a move away from a T1 type response, and a CD4 T cell-mediated regulation of the allocytotoxic T cell response. These results were dependent upon the level of FasL expression on TFC, in that low expression of FasL led to a less marked effect compared with the effect observed with high expression of FasL. These results provide some insight into the role of FasL in regulating destructive alloimmune responses in the case of whole organ grafting, and they have important implications for the development of FasL-based immunotherapy in organ transplantation.	10.1038/35103104	References 26 and 27 show the successful gene transfer of FasL to a specific tissue.
10.1073/pnas.94.8.3943	79,471,500	Binding of CD95 (Fas/APO-1) by its ligand (CD95L) commonly induces apoptosis. Apoptosis of activated T cells, induced by CD95L expressed in the rodent testis, has been proposed to be the mechanism of immune privilege [Bellgrau, D., Gold, D., Selawry, H., Moore, J., Franzusoff, A. & Duke, R. C. (1995) Nature (London) 377, 630–632]. To test whether CD95L could protect pancreatic islet grafts from rejection, we made transgenic mice expressing murine CD95L on their islet β cells and transplanted fetal pancreata under the kidney capsules of allogeneic animals. Expression of CD95L failed to protect the grafts from rejection. However, transgenic mice developed a granulocytic infiltration in their pancreata. These results demonstrate a pro-inflammatory function of CD95L and suggest that expression of CD95L may not be sufficient to protect organ allografts.	10.1038/35103104	This challenges the ability of forced, ectopic expression of FasL to confer immune privilege and also the ability of FasL to protect Sertoli cell transplants.
10.1073/pnas.051566098	65,345,244	The testis is the main source of Fas ligand (FasL) mRNA in rodents; it is generally believed that this molecule, expressed on bordering somatic Sertoli cells, bestows an immune-privileged status in the testis by eliminating infiltrating inflammatory Fas-bearing leukocytes. Our results demonstrate that the attribution of testicular expression of FasL to Sertoli cells is erroneous and that FasL transcription instead occurs in meiotic and postmeiotic germ cells, whereas the protein is only displayed on mature spermatozoa. These findings point to a significant role of the Fas system in the biology of mammalian reproduction.	10.1038/35103104	This shows that FasL is expressed in the spermatogonia, not the Sertoli cells of the testis.
10.1126/science.282.5394.1714	1,778,349	Fas ligand (CD95L) inhibits T cell function in immune-privileged organs such as the eye and testis, yet in most tissues CD95L expression induces potent inflammatory responses. With a stably transfected colon carcinoma cell line, CT26-CD95L, the molecular basis for these divergent responses was defined. When injected subcutaneously, rejection of CT26-CD95L was caused by neutrophils activated by CD95L. CT26-CD95L survived in the intraocular space because of the presence of transforming growth factor–β (TGF-β), which inhibited neutrophil activation. Providing TGF-β to subcutaneous sites protected against tumor rejection. Thus, these cytokines together generate a microenvironment that promotes immunologic tolerance, which may aid in the amelioration of allograft rejection.	10.1038/35103104	The work shows the importance of transforming growth factor-β to the function of FasL as a participant in immune privilege.
10.1126/science.285.5429.898	106,999,840	DNA-damaged cells can either repair the DNA or be eliminated through a homeostatic control mechanism termed “cellular proofreading.” Elimination of DNA-damaged cells after ultraviolet radiation (UVR) through sunburn cell (apoptotic keratinocyte) formation is thought to be pivotal for the removal of precancerous skin cells. Sunburn cell formation was found to be dependent on Fas ligand (FasL), a pro-apoptotic protein induced by DNA damage. Chronic exposure to UVR caused 14 of 20 (70 percent) FasL-deficient mice and 1 of 20 (5 percent) wild-type mice to accumulate p53 mutations in the epidermis. Thus, FasL-mediated apoptosis is important for skin homeostasis, suggesting that the dysregulation of Fas-FasL interactions may be central to the development of skin cancer.	10.1038/35103104	This indicates a role for FasL in controlling skin cancer that is induced by ultraviolet damage.
10.1126/science.1057499	41,569,170	Familial advanced sleep phase syndrome (FASPS) is an autosomal dominant circadian rhythm variant; affected individuals are “morning larks” with a 4-hour advance of the sleep, temperature, and melatonin rhythms. Here we report localization of the FASPS gene near the telomere of chromosome 2q. A strong candidate gene (h Per2 ), a human homolog of the period gene in Drosophila , maps to the same locus. Affected individuals have a serine to glycine mutation within the casein kinase I ɛ (CKI ɛ ) binding region of hPER2, which causes hypophosphorylation by CKI ɛ in vitro. Thus, a variant in human sleep behavior can be attributed to a missense mutation in a clock component, hPER2, which alters the circadian period.	10.1038/35088576	First human mutation that affects circadian rhythmicity is associated with an alteration of PER2 . The altered PER2 protein is hypophosphorylated by casein kinase 1ɛ in vitro
10.1126/science.280.5369.1599	41,693,509	The circadian oscillator generates a rhythmic output with a period of about 24 hours. Despite extensive studies in several model systems, the biochemical mode of action has not yet been demonstrated for any of its components. Here, the Drosophila CLOCK protein was shown to induce transcription of the circadian rhythm genes period and timeless . dCLOCK functioned as a heterodimer with a Drosophila homolog of BMAL1. These proteins acted through an E-box sequence in the period promoter. The timeless promoter contains an 18–base pair element encompassing an E-box, which was sufficient to confer dCLOCK responsiveness to a reporter gene. PERIOD and TIMELESS proteins blocked dCLOCK's ability to transactivate their promoters via the E-box. Thus, dCLOCK drives expression of period and timeless, which in turn inhibit dCLOCK's activity and close the circadian loop.	10.1038/35088576	Establishes that in Drosophila Clock and Cycle positively regulate transcription of per and tim , and that nuclear PER and TIM proteins suppress CLK/CYC activity.
10.1126/science.288.5465.483	62,270,073	The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIɛ), a homolog of the Drosophila circadian gene double-time . In vitro expression and functional studies of wild-type and tau mutant CKIɛ enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIɛ can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIɛ and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.	10.1038/35088576	Cloning of the hamster Tau gene shows that it encodes casein kinase 1ɛ, and that the tau mutation alters phosphorylation and binding to PER in vitro
10.1126/science.288.5468.1013	103,683,055	We show that, in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis of Clock/Clock mutant mice, homozygous Period2 Brdm1 mutants, and Cryptochrome -deficient mice reveals substantially altered Bmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal1 loop. In vitro analysis of CRYPTOCHROME inhibition of CLOCK: BMAL1-mediated transcription shows that the inhibition is through direct protein:protein interactions, independent of the PERIOD and TIMELESS proteins. PERIOD2 is a positive regulator of the Bmal1 loop, and CRYPTOCHROMES are the negative regulators of the Period and Cryptochrome cycles.	10.1038/35088576	Describes the role of PER2 as a positive regulator of Bmal1 expression, and CRY as a negative regulator of Per and Cry expression in mouse tissues.
10.1126/science.291.5503.490	41,570,069	Circadian rhythms of behavior are driven by oscillators in the brain that are coupled to the environmental light cycle. Circadian rhythms of gene expression occur widely in peripheral organs. It is unclear how these multiple rhythms are coupled together to form a coherent system. To study such coupling, we investigated the effects of cycles of food availability (which exert powerful entraining effects on behavior) on the rhythms of gene expression in the liver, lung, and suprachiasmatic nucleus (SCN). We used a transgenic rat model whose tissues express luciferase in vitro. Although rhythmicity in the SCN remained phase-locked to the light-dark cycle, restricted feeding rapidly entrained the liver, shifting its rhythm by 10 hours within 2 days. Our results demonstrate that feeding cycles can entrain the liver independently of the SCN and the light cycle, and they suggest the need to reexamine the mammalian circadian hierarchy. They also raise the possibility that peripheral circadian oscillators like those in the liver may be coupled to the SCN primarily through rhythmic behavior, such as feeding.	10.1038/35088576	References 56 and 57 show that peripheral clocks can be entrained by non-photic stimuli, such as feeding.
10.1126/science.282.5393.1488	80,157,426	Circadian clocks are synchronized by environmental cues such as light. Photoreceptor-deficient Arabidopsis thaliana mutants were used to measure the effect of light fluence rate on circadian period in plants. Phytochrome B is the primary high-intensity red light photoreceptor for circadian control, and phytochrome A acts under low-intensity red light. Cryptochrome 1 and phytochrome A both act to transmit low-fluence blue light to the clock. Cryptochrome 1 mediates high-intensity blue light signals for period length control. The presence of cryptochromes in both plants and animals suggests that circadian input pathways have been conserved throughout evolution.	10.1038/35088576	First report of cryptochromes as circadian photoreceptors in any organism.
10.1126/science.290.5499.2110	62,032,863	Like most organisms, plants have endogenous biological clocks that coordinate internal events with the external environment. We used high-density oligonucleotide microarrays to examine gene expression in Arabidopsis and found that 6% of the more than 8000 genes on the array exhibited circadian changes in steady-state messenger RNA levels. Clusters of circadian-regulated genes were found in pathways involved in plant responses to light and other key metabolic pathways. Computational analysis of cycling genes allowed the identification of a highly conserved promoter motif that we found to be required for circadian control of gene expression. Our study presents a comprehensive view of the temporal compartmentalization of physiological pathways by the circadian clock in a eukaryote.	10.1038/35088576	A comprehensive study of clock-controlled transcription in a eukaryote. It establishes a cis -acting element that mediates clock control of transcription in plants.
10.1126/science.281.5382.1519	62,552,923	Cyanobacteria are the simplest organisms known to have a circadian clock. A circadian clock gene cluster kaiABC was cloned from the cyanobacterium Synechococcus. Nineteen clock mutations were mapped to the three kai genes. Promoter activities upstream of the kaiA and kaiB genes showed circadian rhythms of expression, and both kaiA and kaiBC messenger RNAs displayed circadian cycling. Inactivation of any single kai gene abolished these rhythms and reduced kaiBC -promoter activity. Continuous kaiC overexpression repressed the kaiBC promoter, whereas kaiA overexpression enhanced it. Temporal kaiC overexpression reset the phase of the rhythms. Thus, a negative feedback control of kaiC expression by KaiC generates a circadian oscillation in cyanobacteria, and KaiA sustains the oscillation by enhancing kaiC expression.	10.1038/35088576	First cloning of clock genes in cyanobacteria. The inter-dependent, cycling expression of the three kai genes is shown.
10.1126/science.1060698	125,142,365	Clock:BMAL1 and NPAS2:BMAL1 are heterodimeric transcription factors that control gene expression as a function of the light-dark cycle. Although built to fluctuate at or near a 24-hour cycle, the clock can be entrained by light, activity, or food. Here we show that the DNA-binding activity of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers is regulated by the redox state of nicotinamide adenine dinucleotide (NAD) cofactors in a purified system. The reduced forms of the redox cofactors, NAD(H) and NADP(H), strongly enhance DNA binding of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers, whereas the oxidized forms inhibit. These observations raise the possibility that food, neuronal activity, or both may entrain the circadian clock by direct modulation of cellular redox state.	10.1038/35088576	A possible connection between redox state of a cell and function of NPAS2, a paralogue of CLOCK that is active in circadian clocks of the mammalian forebrain.
10.1126/science.280.5369.1564	20,505,608	The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and is related to transcription factors that act as heterodimers. Potential partners of CLOCK were isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1 at known circadian clock sites in brain and retina. CLOCK-BMAL1 heterodimers activated transcription from E-box elements, a type of transcription factor–binding site, found adjacent to the mouse per1 gene and from an identical E-box known to be important for per gene expression in Drosophila. Mutant CLOCK from the dominant-negative Clock allele and BMAL1 formed heterodimers that bound DNA but failed to activate transcription. Thus, CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.	10.1038/35088576	Establishes in mammals that CLOCK and BMAL1 positively regulate transcription of Per , and that nuclear PER proteins suppress CLOCK/BMAL1 activity.
10.1126/science.289.5480.765	41,524,495	The circadian oscillator of the cyanobacterium Synechococcus elongatus , like those in eukaryotes, is entrained by environmental cues. Inactivation of the gene cikA (circadian input kinase) shortens the circadian period of gene expression rhythms in S . elongatus by approximately 2 hours, changes the phasing of a subset of rhythms, and nearly abolishes resetting of phase by a pulse of darkness. The CikA protein sequence reveals that it is a divergent bacteriophytochrome with characteristic histidine protein kinase motifs and a cryptic response regulator motif. CikA is likely a key component of a pathway that provides environmental input to the circadian oscillator in S . elongatus .	10.1038/35088576	Demonstration of clock function of a two-component response regulator and potential photoreceptor.
10.1084/jem.192.10.1403	26,724,550	The essential upstream steps in granzyme B–mediated apoptosis remain undefined. Herein, we show that granzyme B triggers the mitochondrial apoptotic pathway through direct cleavage of Bid; however, cleavage of procaspases was stalled when mitochondrial disruption was blocked by Bcl-2. The sensitivity of granzyme B–resistant Bcl-2–overexpressing FDC-P1 cells was restored by coexpression of wild-type Bid, or Bid with a mutation of its caspase-8 cleavage site, and both types of Bid were cleaved. However, Bid with a mutated granzyme B cleavage site remained intact and did not restore apoptosis. Bid with a mutation preventing its interaction with Bcl-2 was cleaved but also failed to restore apoptosis. Rapid Bid cleavage by granzyme B (&lt;2 min) was not delayed by Bcl-2 overexpression. These results clearly placed Bid cleavage upstream of mitochondrial Bcl-2. In granzyme B–treated Jurkat cells, endogenous Bid cleavage and loss of mitochondrial membrane depolarization occurred despite caspase inactivation with z-Val-Ala-Asp-fluoromethylketone or Asp-Glu-Val-Asp-fluoromethylketone. Initial partial processing of procaspase-3 and -8 was observed irrespective of Bcl-2 overexpression; however, later processing was completely abolished by Bcl-2. Overall, our results indicate that mitochondrial perturbation by Bid is necessary to achieve a lethal threshold of caspase activity and cell death due to granzyme B.	10.1038/35101078	One of several key articles showing that granzyme B kills target cells by inducing changes in mitochondria.
10.4049/jimmunol.161.5.2195	139,042,073	Abstract We have previously shown that melanoma cells were resistant to apoptosis induced by TNF family members Fas ligand (FasL), TNF-α, and CD40L. FasL also was not involved in CD4 T cell-mediated killing of melanoma cells. In the present study, we have tested melanoma cells for their susceptibility to apoptosis induced by human TNF-related apoptosis-inducing ligand (TRAIL) and the ability of a mAb against TRAIL to inhibit apoptosis and CD4 CTL-mediated killing of melanoma and Jurkat target cells. The results show that TRAIL-induced apoptosis in cells from 7 of 10 melanoma cell lines tested as well as in Jurkat T cells. Susceptibility to apoptosis was increased in some of the cell lines by treatment with cyclohexamide or actinomycin D. The melanoma cells were resistant to apoptosis induced by FasL, TNF-α, and CD40L. mAb M180 against TRAIL inhibited apoptosis induced by TRAIL. It was also found to inhibit CD4 CTL-mediated killing of Jurkat T cells as well as autologous and allogeneic melanoma cells. The degree of inhibition produced by the mAb varied between different clones of CTL and according to the susceptibility of the target cells to TRAIL-induced apoptosis. These results suggest that TRAIL is an important mediator of cell death induced by CTL and may have an important therapeutic role against human melanoma.	10.1038/35101078	This is the first report that CD4 + T cells might kill melanoma by TRAIL-dependent mechanisms.
10.4049/jimmunol.165.10.5612	102,096,352	Abstract Past studies have shown that TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis in a high proportion of cultured melanoma by caspase-dependent mechanisms. In the present studies we have examined whether TRAIL-induced apoptosis of melanoma was mediated by direct activation of effector caspases or whether apoptosis was dependent on changes in mitochondrial membrane potential (MMP) and mitochondrial-dependent pathways of apoptosis. Changes in MMP were measured by fluorescent emission from rhodamine 123 in mitochondria. TRAIL, but not TNF-α or Fas ligand, was shown to induce marked changes in MMP in melanoma, which showed a high correlation with TRAIL-induced apoptosis. This was associated with activation of proapoptotic protein Bid and release of cytochrome c into the cytosol. Overexpression of B cell lymphoma gene 2 (Bcl-2) inhibited TRAIL-induced release of cytochrome c, changes in MMP, and apoptosis. The pan caspase inhibitor z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) and the inhibitor of caspase-8 (z-Ile-Glu-Thr-Asp-fluoromethylketone; zIETD-fmk) blocked changes in MMP and apoptosis, suggesting that the changes in MMP were dependent on activation of caspase-8. Activation of caspase-9 also appeared necessary for TRAIL-induced apoptosis of melanoma. In addition, TRAIL, but not TNF-α or Fas ligand, was shown to induce clustering of mitochondria around the nucleus. This process was not essential for apoptosis but appeared to increase the rate of apoptosis. Taken together, these results suggest that TRAIL induces apoptosis of melanoma cells by recruitment of mitochondrial pathways to apoptosis that are dependent on activation of caspase-8. Therefore, factors that regulate the mitochondrial pathway may be important determinants of TRAIL-induced apoptosis of melanoma.	10.1038/35101078	The first indication that TRAIL-mediated apoptosis occurred by recruitment of mitochondrial death pathways.
10.4049/jimmunol.164.8.3961	17,332,412	Abstract Induction of apoptosis in cells by TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, is believed to be regulated by expression of two death-inducing and two inhibitory (decoy) receptors on the cell surface. In previous studies we found no correlation between expression of decoy receptors and susceptibility of human melanoma cells to TRAIL-induced apoptosis. In view of this, we studied the localization of the receptors in melanoma cells by confocal microscopy to better understand their function. We show that the death receptors TRAIL-R1 and R2 are located in the trans-Golgi network, whereas the inhibitory receptors TRAIL-R3 and -R4 are located in the nucleus. After exposure to TRAIL, TRAIL-R1 and -R2 are internalized into endosomes, whereas TRAIL-R3 and -R4 undergo relocation from the nucleus to the cytoplasm and cell membranes. This movement of decoy receptors was dependent on signals from TRAIL-R1 and -R2, as shown by blocking experiments with Abs to TRAIL-R1 and -R2. The location of TRAIL-R1, -R3, and -R4 in melanoma cells transfected with cDNA for these receptors was similar to that in nontransfected cells. Transfection of TRAIL-R3 and -R4 increased resistance of the melanoma lines to TRAIL-induced apoptosis even in melanoma lines that naturally expressed these receptors. These results indicate that abnormalities in “decoy” receptor location or function may contribute to sensitivity of melanoma to TRAIL-induced apoptosis and suggest that further studies are needed on the functional significance of their nuclear location and TRAIL-induced movement within cells.	10.1038/35101078	A confocal microscopy study of the localization and movement of TRAIL receptors in melanoma and the intracellular signaling involved.
10.4049/jimmunol.166.9.5337	99,477,280	Abstract Previous studies have shown that activation of NF-κB can inhibit apoptosis induced by a number of stimuli. It is also known that TNF-related apoptosis-inducing ligand (TRAIL) can activate NF-κB through the death receptors TRAIL-R1 and TRAIL-R2, and decoy receptor TRAIL-R4. In view of these findings, we have investigated the extent to which activation of NF-κB may account for the variable responses of melanoma lines to apoptosis induced by TRAIL and other TNF family members. Pretreatment of the melanoma lines with the proteasome inhibitor N-acetyl-l-leucinyl-l-leucinyl-l-norleucinal (LLnL), which is known to inhibit activation of NF-κB, was shown to markedly increase apoptosis in 10 of 12 melanoma lines with death receptors for TRAIL. The specificity of results for inhibition of NF-κB activation was supported by an increase of TRAIL-induced apoptosis in melanoma cells transfected with a degradation-resistant IκBα. Furthermore, studies with NF-κB reporter constructs revealed that the resistance of melanoma lines to TRAIL-induced apoptosis was correlated to activation of NF-κB in response to TRAIL. TRAIL-resistant sublines that were generated by intermittent exposure to TRAIL were shown to have high levels of activated NF-κB, and resistance to TRAIL could be reversed by LLnL and by the superrepressor form of IκBα. Therefore, these results suggest that activation of NF-κB by TRAIL plays an important role in resistance of melanoma cells to TRAIL-induced apoptosis and further suggest that inhibitors of NF-κB may be useful adjuncts in clinical use of TRAIL against melanoma.	10.1038/35101078	An important study showing that activation of NF-κB was involved in resistance to TRAIL-induced apoptosis.
10.1046/j.1460-9568.1999.00576.x	41,755,974	Abstract Repeated treatment with psychostimulant drugs produces changes in brain and behaviour that far outlast their initial neuropharmacological actions. The nature of persistent drug‐induced neurobehavioural adaptations is of interest because they are thought to contribute to the development of dependence and addiction, and other forms of psychopathology, e.g. amphetamine psychosis. There are many reports that psychostimulants produce biochemical adaptations in brain monoamine systems, especially dopamine systems. The purpose of the present study was to determine if they might also alter the morphology of neurons in brain regions that receive monoaminergic innervation. Rats were given repeated injections of either amphetamine or cocaine, or, to control for general motor activity, allowed access to a running wheel. They were then left undisturbed for 24–25 days before their brains were processed for Golgi–Cox staining. Treatment with either amphetamine or cocaine (but not wheel running experience) increased the number of dendritic branches and the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens, and on apical dendrites of layer V pyramidal cells in the prefrontal cortex. Cocaine also increased dendritic branching and spine density on the basilar dendrites of pyramidal cells. In addition, both drugs doubled the incidence of branched spines on medium spiny neurons. It is suggested that some of the persistent neurobehavioural consequences of repeated exposure to psychostimulant drugs may be due to their ability to reorganize patterns of synaptic connectivity in the nucleus accumbens and prefrontal cortex.	10.1038/35053570	This study and reference 63 were the first to show that chronic administration of cocaine or the related psychostimulant amphetamine causes alterations in dendritic morphology in specific brain regions. The increases in dendritic length, branch points, and spine density observed in medium spiny neurons of the nucleus accumbens and in pyramidal cells of the prefrontal cortex persist for at least one month after the last drug exposure. Whereas the functional consequences of these changes remain unknown, they could mediate the long-lived sensitization that is observed in behavioural responses to these drugs
10.1146/annurev.neuro.23.1.185	17,590,649	The striatum and its ventral extension, the nucleus accumbens, are involved in behaviors as diverse as motor planning, drug seeking, and learning. Invariably, these striatally mediated behaviors depend on intact dopaminergic innervation. However, the mechanisms by which dopamine modulates neuronal function in the striatum and nucleus accumbens have been difficult to elucidate. Recent electrophysiological studies have revealed that dopamine alters both voltage-dependent conductances and synaptic transmission, resulting in state-dependent modulation of target cells. These studies make clear predictions about how dopamine, particularly via D 1 receptor activation, should alter the responsiveness of striatal neurons to extrinsic excitatory synaptic activity.	10.1038/35053570	A timely review of the physiological effects of dopamine on medium spiny neurons of the nucleus accumbens and dorsal striatum. It discusses dopamine modulation of ion channels through its actions on several subtypes of dopamine receptors. It also covers recent literature on the occurrence of long-term potentiation and long-term depression in these brain regions. Given the central role of dopamine-mediated transmission in drug reinforcement, this review provides a template within which the complex actions of drugs of abuse on the nucleus accumbens can be understood
10.1523/jneurosci.20-15-05575.2000	103,219,999	The mesolimbic dopamine system is essential for reward-seeking behavior, and drugs of abuse are thought to usurp the normal functioning of this pathway. A growing body of evidence suggests that glutamatergic synapses on dopamine neurons in the ventral tegmental area (VTA) are modified during exposure to addictive drugs, producing sensitization, a progressive augmentation in the rewarding properties of psychostimulant drugs with repeated exposure. We have tested the hypothesis that psychostimulant exposure interferes with the synaptic plasticity of glutamatergic inputs to the VTA. We find that excitatory synapses onto VTA dopamine neurons exhibit long-term depression (LTD) in response to low-frequency stimulation and modest depolarization. LTD in the VTA is NMDA receptor-independent but is dependent on intracellular Ca 2+ and can be induced by driving Ca 2+ into the dopamine neuron. Brief exposure to amphetamine entirely blocks LTD at glutamatergic synapses in the VTA, by releasing endogenous dopamine that acts at D2 dopamine receptors. The block of LTD is selective, because amphetamine has no effect on hippocampal LTD. The LTD we have discovered in the VTA is likely to be an important component of excitatory control of the reward pathway; amphetamine will inhibit LTD, removing this normal brake on the glutamatergic drive to dopamine neurons. This effect of amphetamine represents an important mechanism by which normal function of the brain reward system may be impaired during substance abuse.	10.1038/35053570	Shows the development of long-term depression (LTD) at glutamate synapses in the ventral tegmental area (VTA). The authors show that amphetamine, by potentiating the actions of dopamine on D 2 -like receptors, completely abolishes LTD in the VTA. This effect could contribute to the demonstrated ability of amphetamine (and perhaps other drugs of abuse) to potentiate glutamate responses in the VTA (for example, see references 49 88 ) and possibly to cause sensitized behavioural responses as well
10.1523/jneurosci.20-15-05581.2000	81,798,426	Long-lasting adaptations in the mesolimbic dopamine (DA) system in response to drugs of abuse likely mediate many of the behavioral changes that underlie addiction. Recent work suggests that long-term changes in synaptic strength at excitatory synapses in the two major components of this system, the nucleus accumbens (NAc) and ventral tegmental area, may be particularly important for the development of drug-induced sensitization, a process that may contribute to addiction, as well as for normal response-reinforcement learning. Using whole-cell patch-clamp recording techniques from in vitro slice preparations, we have examined the existence and basic mechanisms of long-term depression (LTD) at excitatory synapses on both GABAergic medium spiny neurons in the NAc and dopaminergic neurons in the midbrain. We find that both sets of synapses express LTD but that their basic triggering mechanisms differ. Furthermore, DA blocks the induction of LTD in the midbrain via activation of D2-like receptors but has minimal effects on LTD in the NAc. The existence of LTD in mesolimbic structures and its modulation by DA represent mechanisms that may contribute to the modifications of neural circuitry that mediate reward-related learning as well as the development of addiction.	10.1038/35053570	This study, like reference 84 , shows that long-term depression (LTD) occurs at glutamate synapses in the ventral tegmental area (VTA), and that LTD is inhibited by dopamine acting at D 2 -like receptors. The authors also show LTD at glutamatergic synapses on medium spiny neurons of the nucleus accumbens, although no effect of dopamine on LTD was seen in this region
10.1073/pnas.91.5.1927	19,771,222	The SRY gene on the human, mouse, and marsupial Y chromosomes is the testis-determining gene that initiates male development in mammals. The SRY protein has a DNA-binding domain (high mobility group or HMG box) similar to those found in the high-mobility-group proteins. SRY is specific for the Y chromosome, but many autosomal genes have been identified that possess a similar HMG box region; those with the most closely SRY-related box regions form a gene family now referred to as SOX genes. We have identified a sequence on the marsupial X chromosome that shares homology with SRY. Sequence comparisons show near-identity with the mouse and human SOX3 gene (formerly called a3), the SOX gene which is the most closely related to SRY. We suggest here that the highly conserved X chromosome-linked SOX3 represents the ancestral SOX gene from which the sex-determining gene SRY was derived. In this model SOX3/SRY divergence and the acquisition of a testis-determining role by SRY might have preceded (and initiated) sex chromosome differentiation or, alternatively, might have been a consequence of X chromosome-Y chromosome differentiation initiated at the locus of an original sex-determining gene(s), later superseded by SRY.	10.1038/35056058	References 8 and 9 together identify SOX3 as the X-chromosome homologue of the male-determining gene SRY , and show that the SRY – SOX3 split probably initiated the X–Y divergence in mammalian ancestors.
10.1126/science.286.5441.964	62,428,712	Human sex chromosomes evolved from autosomes. Nineteen ancestral autosomal genes persist as differentiated homologs on the X and Y chromosomes. The ages of individual X-Y gene pairs (measured by nucleotide divergence) and the locations of their X members on the X chromosome were found to be highly correlated. Age decreased in stepwise fashion from the distal long arm to the distal short arm in at least four “evolutionary strata.” Human sex chromosome evolution was probably punctuated by at least four events, each suppressing X-Y recombination in one stratum, without disturbing gene order on the X chromosome. The first event, which marked the beginnings of X-Y differentiation, occurred about 240 to 320 million years ago, shortly after divergence of the mammalian and avian lineages.	10.1038/35056058	This paper shows that X and Y chromosomes in the human lineage ceased to recombine with each other in progressive blocks during evolution.
10.1073/pnas.97.13.7354	38,578,187	Some insight into human evolution has been gained from the sequencing of four Y chromosome genes. Primary genomic sequencing determined gene SMCY to be composed of 27 exons that comprise 4,620 bp of coding sequence. The unfinished sequencing of the 5′ portion of gene UTY1 was completed by primer walking, and a total of 20 exons were found. By using denaturing HPLC, these two genes, as well as DBY and DFFRY , were screened for polymorphic sites in 53–72 representatives of the five continents. A total of 98 variants were found, yielding nucleotide diversity estimates of 2.45 × 10 −5 , 5.07 × 10 −5 , and 8.54 × 10 −5 for the coding regions of SMCY , DFFRY , and UTY1 , respectively, with no variant having been observed in DBY . In agreement with most autosomal genes, diversity estimates for the noncoding regions were about 2- to 3-fold higher and ranged from 9.16 × 10 −5 to 14.2 × 10 −5 for the four genes. Analysis of the frequencies of derived alleles for all four genes showed that they more closely fit the expectation of a Luria–Delbrück distribution than a distribution expected under a constant population size model, providing evidence for exponential population growth. Pairwise nucleotide mismatch distributions date the occurrence of population expansion to ≈28,000 years ago. This estimate is in accord with the spread of Aurignacian technology and the disappearance of the Neanderthals.	10.1038/35056058	This paper, from a research group which has made considerable use of non-genic non-recombining Y region (NRY) sequence variation to infer aspects of human population history, summarizes the current understanding of human Y-chromosome population genetics using new data on sequence variation in NRY genes themselves.
10.1126/science.8284674	80,659,179	Comparative studies suggest that sex chromosomes begin as ordinary autosomes that happen to carry a major sex determining locus. Over evolutionary time the Y chromosome is selected to stop recombining with the X chromosome, perhaps in response to accumulation of alleles beneficial to the heterogametic but harmful to the homogametic sex. Population genetic theory predicts that a nonrecombining Y chromosome should degenerate. Here this prediction is tested by application of specific selection pressures to Drosophila melanogaster populations. Results demonstrate the decay of a nonrecombining, nascent Y chromosome and the capacity for recombination to ameliorate such decay.	10.1038/35056058	Experimental evidence that the suppression of recombination is detrimental to the functional integrity of genes in diploid organisms.

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