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See detailInositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells.
Maréchal, Y.; Pesesse, X.; Jia, Y. et al

in Proceedings of the National Academy of Sciences of the United States of America (2007), 104

The contribution of the B isoform of inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] 3-kinase (or Itpkb) and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)], its reaction product, to B cell function ... [more ▼]

The contribution of the B isoform of inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] 3-kinase (or Itpkb) and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)], its reaction product, to B cell function and development remains unknown. Here, we show that mice deficient in Itpkb have defects in B cell survival leading to specific and intrinsic developmental alterations in the B cell lineage and antigen unresponsiveness in vivo. The decreased B cell survival is associated with a decreased phosphorylation of Erk1/2 and increased Bim gene expression. B cell survival, development, and antigen responsiveness are normalized in parallel to reduced expression of Bim in Itpkb(-/-) Bim(+/-) mice. Analysis of the signaling pathway downstream of Itpkb revealed that Ins(1,3,4,5)P(4) regulates subcellular distribution of Rasa3, a Ras GTPase-activating protein acting as an Ins(1,3,4,5)P(4) receptor. Together, our results indicate that Itpkb and Ins(1,3,4,5)P(4) mediate a survival signal in B cells via a Rasa3-Erk signaling pathway controlling proapoptotic Bim gene expression [less ▲]

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See detailTranscranial magnetic stimulation of the visual cortex induces somatotopically organized qualia in blind subjects
Kupers, R.; Fumal, Arnaud ULg; Maertens De Noordhout, Alain ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(35), 13256-13260

After loss of a particular sensory channel, the deprived cortex can be activated by inputs from other sensory modalities. It is not known whether activation of the rewired cortex evokes subjective ... [more ▼]

After loss of a particular sensory channel, the deprived cortex can be activated by inputs from other sensory modalities. It is not known whether activation of the rewired cortex evokes subjective experiences characteristic of that cortex or consistent with the rerouted sensory information. In a previous study, blind subjects were trained to perform visual tasks with a tongue display unit, a sensory substitution device that translates visual displays into electrotactile tongue stimulation. This cross-modal sensory stimulation activated their visual cortices. We now extend this finding by using transcranial magnetic stimulation to examine the perceptual correlates of training-induced plastic responses. We find that blind subjects proficient with the use of the tongue display unit report somatopicaily organized tactile sensations that are referred to the tongue when transcranial magnetic stimulation is applied over the occipital cortex. No such sensations were evoked in trained, blindfolded, seeing control subjects who performed the sensory substitution task equally well. These data show that the perceptual correlate of activity in a given cortical area reflects the characteristics of its novel sensory input source. [less ▲]

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See detailSleep after spatial learning promotes covert reorganization of brain activity
Orban, Pierre ULg; Rauchs, Géraldine; Balteau, Evelyne ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(18), 7124-7129

Sleep promotes the integration of recently acquired spatial memories into cerebral networks for the long term. In this study, we examined how sleep deprivation hinders this consolidation process. Using ... [more ▼]

Sleep promotes the integration of recently acquired spatial memories into cerebral networks for the long term. In this study, we examined how sleep deprivation hinders this consolidation process. Using functional MRI, we mapped regional cerebral activity during place-finding navigation in a virtual town, immediately after learning and 3 days later, in subjects either allowed regular sleep (RS) or totally sleep-deprived (TSD) on the first posttraining night. At immediate and delayed retrieval, place-finding navigation elicited increased brain activity in an extended hippocamponeocortical network in both RS and TSD subjects. Behavioral performance was equivalent between groups. However, striatal navigation-related activity increased more at delayed retrieval in RS than in TSD subjects. Furthermore, correlations between striatal response and behavioral performance, as well as functional connectivity between the striatum and the hippocampus, were modulated by posttraining sleep. These data suggest that brain activity is restructured during sleep in such a way that navigation in the virtual environment, initially related to a hippocampus-dependent spatial strategy, becomes progressively contingent in part on a response-based strategy mediated by the striatum. Both neural strategies eventually relate to equivalent performance levels, indicating that covert reorganization of brain patterns underlying navigation after sleep is not necessarily accompanied by overt changes in behavior. [less ▲]

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See detailHigh-efficiency biolistic transformation of Chlamydomonas mitochondria can be used to insert mutations in complex I genes
Remacle, Claire ULg; Cardol, Pierre ULg; Coosemans, Nadine ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(12), 4771-4776

Mitochondrial transformation of Chlamydomonas reinhardtii has been optimized by using a particle-gun device and cloned mitochondrial DNA or PCR fragments. A respiratory-deficient strain lacking a 1.2-kb ... [more ▼]

Mitochondrial transformation of Chlamydomonas reinhardtii has been optimized by using a particle-gun device and cloned mitochondrial DNA or PCR fragments. A respiratory-deficient strain lacking a 1.2-kb mitochondrial DNA region including the left telomere and part of the cob gene could be rescued as well as a double-frameshift mutant in the mitochondrial cox1 and nd1 genes. High transformation efficiency has been achieved (100-250 transformants per microgram of DNA), the best results being obtained with linearized plasmid DNA. Molecular analysis of the transformants suggests that the right telomere sequence can be copied to reconstruct the left telomere by recombination. In addition, both nondeleterious and deleterious mutations could be introduced. Myxothiazol-resistant transformants have been created by introducing a nucleotide substitution into the cob gene. Similarly, an in-frame deletion of 23 codons has been created in the nd4 mitochondrial gene of both the deleted and frameshift recipient strains. These 23 codons are believed to encode the first transmembrane segment of the ND4 protein. This Delta nd4 mutation causes a misassembly of complex 1, with the accumulation of a subcomplex that is 250-kDa smaller than the wild-type complex 1. The availability of efficient mitochondrial transformation in Chlamydomonas provides an invaluable tool for the study of mitochondrial biogenesis and, more specifically, for site-directed mutagenesis of mitochondrially encoded subunits of complex 1, of special interest because the yeast Saccharomyces cerevisiae, whose mitochondrial genome can be manipulated virtually at will, is lacking complex 1. [less ▲]

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See detailA northern glacial refugium for bank voles (Clethrionomys glareolus).
Kotlìk, Petr; Deffontaine Deurbroeck, Valérie ULg; Mascheretti, Silvia et al

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(40), 14860-14864

There is controversy and uncertainty on how far north there were glacial refugia for temperate species during the Pleistocene glaciations and in the extent of the contribution of such refugia to present ... [more ▼]

There is controversy and uncertainty on how far north there were glacial refugia for temperate species during the Pleistocene glaciations and in the extent of the contribution of such refugia to present-day populations. We examined these issues using phylogeographic analysis of a European woodland mammal, the bank vole (Clethrionomys glareolus). A Bayesian coalescence analysis indicates that a bank vole population survived the height of the last glaciation (≈25,000–10,000 years B.P.) in the vicinity of the Carpathians, a major central European mountain chain well north of the Mediterranean areas typically regarded as glacial refugia for temperate species. Parameter estimates from the fitted isolation with migration model show that the divergence of the Carpathian population started at least 22,000 years ago, and it was likely followed by only negligible immigration from adjacent regions, suggesting the persistence of bank voles in the Carpathians through the height of the last glaciation. On the contrary, there is clear evidence for gene flow out of the Carpathians, demonstrating the contribution of the Carpathian population to the colonization of Europe after the Pleistocene. These findings are consistent with data from animal and plant fossils recovered in the Carpathians and provide the clearest phylogeographic evidence to date of a northern glacial refugium for temperate species in Europe. [less ▲]

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See detailCoupling of cell migration with neurogenesis by proneural bHLH factors.
Ge, Weihong; He, Fei; Kim, Kevin J. et al

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(5), 1319-24

After cell birth, almost all neurons in the mammalian central nervous system migrate. It is unclear whether and how cell migration is coupled with neurogenesis. Here we report that proneural basic helix ... [more ▼]

After cell birth, almost all neurons in the mammalian central nervous system migrate. It is unclear whether and how cell migration is coupled with neurogenesis. Here we report that proneural basic helix-loop-helix (bHLH) transcription factors not only initiate neuronal differentiation but also potentiate cell migration. Mechanistically, proneural bHLH factors regulate the expression of genes critically involved in migration, including down-regulation of RhoA small GTPase and up-regulation of doublecortin and p35, which, in turn, modulate the actin and microtubule cytoskeleton assembly and enable newly generated neurons to migrate. In addition, we report that several DNA-binding-deficient proneural genes that fail to initiate neuronal differentiation still activate migration, whereas a different mutation of a proneural gene that causes a failure in initiating cell migration still leads to robust neuronal differentiation. Collectively, these data suggest that transcription programs for neurogenesis and migration are regulated by bHLH factors through partially distinct mechanisms. [less ▲]

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See detailAn electronic time scale in chemistry
Remacle, Françoise ULg; Levine, R. D.

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(18), 6793-6798

Ultrafast, subfemtosecond charge migration in small peptides is discussed on the basis of computational studies and compared with the selective bond dissociation after ionization as observed by Schlag and ... [more ▼]

Ultrafast, subfemtosecond charge migration in small peptides is discussed on the basis of computational studies and compared with the selective bond dissociation after ionization as observed by Schlag and Weinkauf. The reported relaxation could be probed in real time if the removal of an electron could be achieved on the attosecond time scale. Then the mean field seen by an electron would be changing rapidly enough to initiate the migration. Tyrosine-terminated tetrapeptides have a particularly fast charge migration where in < 1 fs the charge arrives at the other end. A femtosecond pulse can be used to observe the somewhat slower relaxation induced by correlation between electrons of different spins. A slower relaxation also is indicated when removing a deeper-lying valence electron. When a chromophoric amino acid is at one end of the peptide, the charge can migrate all along the peptide backbone up to the N end, but site-selective ionization is probably easier to detect for tryptophan than for tyrosine. [less ▲]

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See detailProlactin/growth hormone-derived antiangiogenic peptides highlight a potential role of tilted peptides in angiogenesis
Nguyen, Ngoc-Quynh-Nhu ULg; Tabruyn, Sébastien ULg; Lins, Laurence ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(39), 14319-14324

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short ... [more ▼]

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short peptides known to destabilize membranes and lipid cores and characterized by an asymmetric distribution of hydrophobic residues along the axis when helical. We have previously shown that 16-kDa fragments of the human prolactin/growth hormone (PRL/GH) family members are potent angiogenesis inhibitors. Here, we demonstrate that all these fragments possess a 14-aa sequence having the characteristics of a tilted peptide. The tilted peptides of human prolactin and human growth hormone induce endothelial cell apoptosis, inhibit endothelial cell proliferation, and inhibit capillary formation both in vitro and in vivo. These antiangiogenic effects are abolished when the peptides' hydrophobicity gradient is altered by mutation. We further demonstrate that the well known tilted peptides of simian immunodeficiency virus gp32 and Alzheimer's beta-amyloid peptide are also angiogenesis inhibitors. Taken together, these results point to a potential new role for tilted peptides in regulating angiogenesis. [less ▲]

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See detailTransgenic engineering of male-specific muscular hypertrophy.
Pirottin, Dimitri ULg; Grobet, Luc ULg; Adamantidis, Antoine ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2005), 102(18), 6413-8

Using a two-step procedure involving insertional gene targeting and recombinase-mediated cassette exchange in ES cells, we have produced two lines of transgenic mice expressing a dominant-negative latency ... [more ▼]

Using a two-step procedure involving insertional gene targeting and recombinase-mediated cassette exchange in ES cells, we have produced two lines of transgenic mice expressing a dominant-negative latency-associated myostatin propeptide under control of the myosin light chain 1F promoter and 1/3 enhancer from the TSPY locus on the Y chromosome. Males of the corresponding lines are characterized by a 5-20% increase in skeletal muscle mass. This experiment demonstrates the feasibility of a more efficient cattle production system combining superior beef production abilities for bulls and dairy abilities for cows. [less ▲]

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See detailStructure of the light chain-binding domain of myosin V.
Terrak, Mohammed ULg; Rebowski, Grzegorz; Lu, Renne C et al

in Proceedings of the National Academy of Sciences of the United States of America (2005), 102(36), 12718-23

Myosin V is a double-headed molecular motor involved in organelle transport. Two distinctive features of this motor, processivity and the ability to take extended linear steps of approximately 36 nm along ... [more ▼]

Myosin V is a double-headed molecular motor involved in organelle transport. Two distinctive features of this motor, processivity and the ability to take extended linear steps of approximately 36 nm along the actin helical track, depend on its unusually long light chain-binding domain (LCBD). The LCBD of myosin V consists of six tandem IQ motifs, which constitute the binding sites for calmodulin (CaM) and CaM-like light chains. Here, we report the 2-A resolution crystal structure of myosin light chain 1 (Mlc1p) bound to the IQ2-IQ3 fragment of Myo2p, a myosin V from Saccharomyces cerevisiae. This structure, combined with FRET distance measurements between probes in various CaM-IQ complexes, comparative sequence analysis, and the previously determined structures of Mlc1p-IQ2 and Mlc1p-IQ4, allowed building a model of the LCBD of myosin V. The IQs of myosin V are distributed into three pairs. There appear to be specific cooperative interactions between light chains within each IQ pair, but little or no interaction between pairs, providing flexibility at their junctions. The second and third IQ pairs each present a light chain, whether CaM or a CaM-related molecule, bound in a noncanonical extended conformation in which the N-lobe does not interact with the IQ motif. The resulting free N-lobes may engage in protein-protein interactions. The extended conformation is characteristic of the single IQ of myosin VI and is common throughout the myosin superfamily. The model points to a prominent role of the LCBD in the function, regulation, and molecular interactions of myosin V. [less ▲]

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See detailActin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly.
Chereau, David; Kerff, Frédéric ULg; Graceffa, Philip et al

in Proceedings of the National Academy of Sciences of the United States of America (2005), 102(46), 16644-9

Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 (WH2) is a small and widespread actin-binding motif. In the WASP family, WH2 plays a role in filament nucleation by Arp2/3 complex. Here we ... [more ▼]

Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 (WH2) is a small and widespread actin-binding motif. In the WASP family, WH2 plays a role in filament nucleation by Arp2/3 complex. Here we describe the crystal structures of complexes of actin with the WH2 domains of WASP, WASP-family verprolin homologous protein, and WASP-interacting protein. Despite low sequence identity, WH2 shares structural similarity with the N-terminal portion of the actin monomer-sequestering thymosin beta domain (Tbeta). We show that both domains inhibit nucleotide exchange by targeting the cleft between actin subdomains 1 and 3, a common binding site for many unrelated actin-binding proteins. Importantly, WH2 is significantly shorter than Tbeta but binds actin with approximately 10-fold higher affinity. WH2 lacks a C-terminal extension that in Tbeta4 becomes involved in monomer sequestration by interfering with intersubunit contacts in F-actin. Owing to their shorter length, WH2 domains connected in tandem by short linkers can coexist with intersubunit contacts in F-actin and are proposed to function in filament nucleation by lining up actin subunits along a filament strand. The WH2-central region of WASP-family proteins is proposed to function in an analogous way by forming a special class of tandem repeats whose function is to line up actin and Arp2 during Arp2/3 nucleation. The structures also suggest a mechanism for how profilin-binding Pro-rich sequences positioned N-terminal to WH2 could feed actin monomers directly to WH2, thereby playing a role in filament elongation. [less ▲]

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See detailReplication-associated strand asymmetries in mammalian genomes: Toward detection of replication origins
Touchon, M.; Nicolay, Samuel ULg; Audit, B. et al

in Proceedings of the National Academy of Sciences of the United States of America (2005), 102(28), 9836-9841

In the course of evolution, mutations do not affect both strands of genomic DNA equally. This imbalance mainly results from asym- metric DNA mutation and repair processes associated with repli- cation and ... [more ▼]

In the course of evolution, mutations do not affect both strands of genomic DNA equally. This imbalance mainly results from asym- metric DNA mutation and repair processes associated with repli- cation and transcription. In prokaryotes, prevalence of G over C and T over A is frequently observed in the leading strand. The sign of the resulting TA and GC skews changes abruptly when crossing replication-origin and termination sites, producing characteristic step-like transitions. In mammals, transcription-coupled skews have been detected, but so far, no bias has been associated with replication. Here, analysis of intergenic and transcribed regions flanking experimentally identified human replication origins and the corresponding mouse and dog homologous regions demon- strates the existence of compositional strand asymmetries associ- ated with replication. Multiscale analysis of human genome skew profiles reveals numerous transitions that allow us to identify a set of 1,000 putative replication initiation zones. Around these puta- tive origins, the skew profile displays a characteristic jagged pattern also observed in mouse and dog genomes. We therefore propose that in mammalian cells, replication termination sites are randomly distributed between adjacent origins. Taken together, these analyses constitute a step toward genome-wide studies of replication mechanisms. [less ▲]

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See detailValproate activates bovine leukemia virus gene expression, triggers apoptosis, and induces leukemia/lymphoma regression in vivo.
Achachi, Amine; Florins, Arnaud-Francois ULg; Gillet, Nicolas ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2005), 102(29), 10309-14

Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV) presumably persist in the host partly by latent integration of the provirus in a fraction of infected cells, leading to ... [more ▼]

Leukemogenic viruses like human T-lymphotropic virus and bovine leukemia virus (BLV) presumably persist in the host partly by latent integration of the provirus in a fraction of infected cells, leading to accumulative increase in the outgrowth of transformed cells. Furthermore, viral infection also correlates with a blockade of the apoptotic mechanisms concomitant with an apparent latency of the host cell. Conceptually, induction of viral or cellular gene expression could thus also be used as a therapeutic strategy against retroviral-associated leukemia. Here, we provide evidence that valproate, an inhibitor of deacetylases, activates BLV gene expression in transient transfection experiments and in short-term cultures of primary B-lymphocytes. In vivo, valproate injection into newly BLV-inoculated sheep did not abrogate primary infection. However, valproate treatment, in the absence of any other cytotoxic drug, was efficient for leukemia/lymphoma therapy in the sheep model leading to decreased lymphocyte numbers (respectively from 25.6, 35.7, and 46.5 x 10(3) cells per mm3 to 1.0, 10.6, and 24.3 x 10(3) cells per mm3 in three leukemic sheep) and tumor regression (from >700 cm3 to undetectable). The concept of a therapy that targets the expression of viral and cellular genes might be a promising treatment of adult T cell leukemia or tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy, diseases for which no satisfactory treatment exists so far. [less ▲]

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See detailSuppression Of Tumor Growth And Cell Proliferation By P13(Ii), A Mitochondrial Protein Of Human T Cell Leukemia Virus Type 1
Silic-Benussi, M.; Cavallari, L.; Zorzan, T. et al

in Proceedings of the National Academy of Sciences of the United States of America (2004), 101(17),

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See detailGenetic and functional confirmation of the causality of the DGAT1 K232A quantitative trait nucleotide in affecting milk yield and composition
Grisart, B.; Farnir, Frédéric ULg; Karim, Latifa ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2004), 101(8), 2398-2403

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (K232A) in the bovine DGAT1 gene that was proposed to be the causative quantitative trait ... [more ▼]

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (K232A) in the bovine DGAT1 gene that was proposed to be the causative quantitative trait nucleotide underlying a quantitative trait locus (QTL) affecting milk fat composition, previously mapped to the centromeric end of bovine chromosome 14. We herein generate genetic and functional data that confirm the causality of the DGAT1 K232A mutation. We have constructed a high-density single-nucleotide polymorphism map of the 3.8-centimorgan BULGE30-BULGE9 interval containing the QTL and show that the association with milk fat percentage maximizes at the DGAT1 gene. We provide evidence that the K allele has undergone a selective sweep. By using a baculovirus expression system, we have expressed both DGAT1 alleles in Sf9 cells and show that the K allele, causing an increase in milk fat percentage in the live animal, is characterized by a higher V-max in producing triglycerides than the A allele. [less ▲]

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See detailIncreased Cell Proliferation, But Not Reduced Cell Death, Induces Lymphocytosis In Bovine Leukemia Virus-Infected Sheep
Debacq, C.; Asquith, B.; Kerkhofs, P. et al

in Proceedings of the National Academy of Sciences of the United States of America (2002), 99(15),

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See detailPDX:PBX complexes are required for normal proliferation of pancreatic cells during development.
Dutta, S.; Gannon, M.; Peers, Bernard ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2001), 98(3), 1065-70

The homeobox factor PDX-1 is a key regulator of pancreatic morphogenesis and glucose homeostasis; targeted disruption of the PDX-1 gene leads to pancreatic agenesis in pdx-1(-/-) homozygotes. Pdx-1 ... [more ▼]

The homeobox factor PDX-1 is a key regulator of pancreatic morphogenesis and glucose homeostasis; targeted disruption of the PDX-1 gene leads to pancreatic agenesis in pdx-1(-/-) homozygotes. Pdx-1 heterozygotes develop normally, but they display glucose intolerance in adulthood. Like certain other homeobox proteins, PDX-1 contains a consensus FPWMK motif that promotes heterodimer formation with the ubiquitous homeodomain protein PBX. To evaluate the importance of PDX-1:PBX complexes in pancreatic morphogenesis and glucose homeostasis, we expressed either wild-type or PBX interaction defective PDX-1 transgenes under control of the PDX-1 promoter. Both wild-type and mutant PDX-1 transgenes corrected glucose intolerance in pdx-1 heterozygotes. The wild-type PDX-1 transgene rescued the development of all pancreatic lineages in pdx-1(-/-) animals, and these mice survived to adulthood. In contrast, pancreata from pdx-1(-/-) mice expressing the mutant PDX-1 transgene were hypoplastic, and these mice died within 3 weeks of birth from pancreatic insufficiency. All pancreatic cell types were observed in pdx-1(-/-) mice expressing the mutant PDX-1 transgene; but the islets were smaller, and increased numbers of islet hormone-positive cells were noted within the ductal epithelium. These results indicate that PDX-1:PBX complexes are dispensable for glucose homeostasis and for differentiation of stem cells into ductal, endocrine, and acinar lineages; but they are essential for expansion of these populations during development. [less ▲]

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See detailAnalysis Of The Chromosome Sequence Of The Legume Symbiont Sinorhizobium Meliloti Strain 1021
Capela, Delphine; Barloy-Hubler, Frédérique; Gouzy, Jérôme et al

in Proceedings of the National Academy of Sciences of the United States of America (2001), 98(17),

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See detailCIKS, a connection to Ikappa B kinase and stress-activated protein kinase.
Leonardi, Antonio; Chariot, Alain ULg; Claudio, Estefania et al

in Proceedings of the National Academy of Sciences of the United States of America (2000), 97(19), 10494-10499

Pathogens, inflammatory signals, and stress cause acute transcriptional responses in cells. The induced expression of genes in response to these signals invariably involves transcription factors of the NF ... [more ▼]

Pathogens, inflammatory signals, and stress cause acute transcriptional responses in cells. The induced expression of genes in response to these signals invariably involves transcription factors of the NF-kappaB and AP-1/ATF families. Activation of NF-kappaB factors is thought to be mediated primarily via IkappaB kinases (IKK), whereas that of AP-1/ATF can be mediated by stress-activated protein kinases (SAPKs; also named Jun kinases or JNKs). IKKalpha and IKKbeta are two catalytic subunits of a core IKK complex that also contains the regulatory subunit NEMO (NF-kappaB essential modulator)/IKKgamma. The latter protein is essential for activation of the IKKs, but its mechanism of action is not known. Here we describe the molecular cloning of CIKS (connection to IKK and SAPK/JNK), a previously unknown protein that directly interacts with NEMO/IKKgamma in cells. When ectopically expressed, CIKS stimulates IKK and SAPK/JNK kinases and it transactivates an NF-kappaB-dependent reporter. Activation of NF-kappaB is prevented in the presence of kinase-deficient, interfering mutants of the IKKs. CIKS may help to connect upstream signaling events to IKK and SAPK/JNK modules. CIKS could coordinate the activation of two stress-induced signaling pathways, functions reminiscent of those noted for tumor necrosis factor receptor-associated factor adaptor proteins. [less ▲]

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See detailA Multipotential Beta -1,6-N-Acetylglucosaminyl-Transferase Is Encoded by Bovine Herpesvirus Type 4
Vanderplasschen, Alain ULg; Markine-Goriaynoff, N.; Lomonte, P. et al

in Proceedings of the National Academy of Sciences of the United States of America (2000), 97(11), 5756-5761

The beta-1,6-N-acetylglucosaminyltransferase (beta1,6GnT) gene family encodes enzymes playing crucial roles in glycan synthesis. Important changes in beta1,6GnT expression are observed during development ... [more ▼]

The beta-1,6-N-acetylglucosaminyltransferase (beta1,6GnT) gene family encodes enzymes playing crucial roles in glycan synthesis. Important changes in beta1,6GnT expression are observed during development, oncogenesis, and immunodeficiency. The most characterized beta1,6GnTs in this gene family are the human (h) C2GnT-L and h-IGnT, which have core 2 [Galbeta1-->3(GlcNAcbeta1-->6)GalNAc] and I branching [GlcNAcbeta1-->3(GlcNAcbeta1-->6)Gal] activities, respectively. Recently, h-C2GnT-M was shown to be unique in forming core 2, core 4 [GlcNAcbeta1-->3(GlcNAcbeta1-->6)GalNAc], and I structures. To date, the beta1,6GnT gene family has been characterized only in mammals. Here, we describe that bovine herpesvirus type 4 (BHV-4) encodes a beta1,6GnT expressed during viral replication and exhibiting all of the core 2, core 4, and I branching activities. Sequencing of the BHV-4 genome revealed an ORF, hereafter called BORFF3-4, encoding a protein (pBORFF3-4) exhibiting 81.1%, 50.7%, and 36.6% amino acid identity with h-C2GnT-M, h-C2GnT-L, and h-IGnT, respectively. Reverse transcriptase-PCR analysis revealed that BORFF3-4 is expressed during BHV-4 replication. Expression of BORFF3-4 in Chinese hamster ovary cells directed the expression of core 2 branched oligosaccharides and I antigenic structures on the cell surface. Moreover, a soluble form of pBORFF3-4 had core 4 branching activity in addition to core 2 and I branching activities. Finally, infection of a C2GnT-negative cell line with BHV-4 induced expression of core 2 branched oligosaccharides. This study extends the beta1,6GnT gene family to a viral gene and provides a model to study the biological functions of a beta1,6GnT in the context of viral infection. [less ▲]

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