Showing papers in "Nature in 1999"
TL;DR: An algorithm for non-negative matrix factorization is demonstrated that is able to learn parts of faces and semantic features of text and is in contrast to other methods that learn holistic, not parts-based, representations.
Abstract: Is perception of the whole based on perception of its parts? There is psychological and physiological evidence for parts-based representations in the brain, and certain computational theories of object recognition rely on such representations. But little is known about how brains or computers might learn the parts of objects. Here we demonstrate an algorithm for non-negative matrix factorization that is able to learn parts of faces and semantic features of text. This is in contrast to other methods, such as principal components analysis and vector quantization, that learn holistic, not parts-based, representations. Non-negative matrix factorization is distinguished from the other methods by its use of non-negativity constraints. These constraints lead to a parts-based representation because they allow only additive, not subtractive, combinations. When non-negative matrix factorization is implemented as a neural network, parts-based representations emerge by virtue of two properties: the firing rates of neurons are never negative and synaptic strengths do not change sign.
11,500 citations
TL;DR: The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelIn, a peptide specifically releases GH both in vivo and in vitro.
Abstract: Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through GHS-R, a G-protein-coupled receptor for which the ligand is unknown. Recent cloning of GHS-R strongly suggests that an endogenous ligand for the receptor does exist and that there is a mechanism for regulating GH release that is distinct from its regulation by hypothalamic growth-hormone-releasing hormone (GHRH). We now report the purification and identification in rat stomach of an endogenous ligand specific for GHS-R. The purified ligand is a peptide of 28 amino acids, in which the serine 3 residue is n-octanoylated. The acylated peptide specifically releases GH both in vivo and in vitro, and O-n-octanoylation at serine 3 is essential for the activity. We designate the GH-releasing peptide 'ghrelin' (ghre is the Proto-Indo-European root of the word 'grow'). Human ghrelin is homologous to rat ghrelin apart from two amino acids. The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelin.
8,073 citations
TL;DR: In this article, an organic dicarboxylate linker is used in a reaction that gives supertetrahedron clusters when capped with monocarboxyates.
Abstract: Open metal–organic frameworks are widely regarded as promising materials for applications1,2,3,4,5,6,7,8,9,10,11,12,13,14,15 in catalysis, separation, gas storage and molecular recognition. Compared to conventionally used microporous inorganic materials such as zeolites, these organic structures have the potential for more flexible rational design, through control of the architecture and functionalization of the pores. So far, the inability of these open frameworks to support permanent porosity and to avoid collapsing in the absence of guest molecules, such as solvents, has hindered further progress in the field14,15. Here we report the synthesis of a metal–organic framework which remains crystalline, as evidenced by X-ray single-crystal analyses, and stable when fully desolvated and when heated up to 300?°C. This synthesis is achieved by borrowing ideas from metal carboxylate cluster chemistry, where an organic dicarboxylate linker is used in a reaction that gives supertetrahedron clusters when capped with monocarboxylates. The rigid and divergent character of the added linker allows the articulation of the clusters into a three-dimensional framework resulting in a structure with higher apparent surface area and pore volume than most porous crystalline zeolites. This simple and potentially universal design strategy is currently being pursued in the synthesis of new phases and composites, and for gas-storage applications.
6,778 citations
TL;DR: Research in the use of organic polymers as active semiconductors in light-emitting diodes has advanced rapidly, and prototype devices now meet realistic specifications for applications.
Abstract: Research in the use of organic polymers as the active semiconductors in light-emitting diodes has advanced rapidly, and prototype devices now meet realistic specifications for applications. These achievements have provided insight into many aspects of the background science, from design and synthesis of materials, through materials fabrication issues, to the semiconductor physics of these polymers.
5,653 citations
TL;DR: It is shown that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets, which are named central memory (TCM) and effector memory (TEM).
Abstract: Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.
5,537 citations
TL;DR: The recent completion of drilling at Vostok station in East Antarctica has allowed the extension of the ice record of atmospheric composition and climate to the past four glacial-interglacial cycles as discussed by the authors.
Abstract: The recent completion of drilling at Vostok station in East Antarctica has allowed the extension of the ice record of atmospheric composition and climate to the past four glacial–interglacial cycles. The succession of changes through each climate cycle and termination was similar, and atmospheric and climate properties oscillated between stable bounds. Interglacial periods differed in temporal evolution and duration. Atmospheric concentrations of carbon dioxide and methane correlate well with Antarctic air-temperature throughout the record. Present-day atmospheric burdens of these two important greenhouse gases seem to have been unprecedented during the past 420,000 years.
5,109 citations
TL;DR: It is indicated that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF α-subunits, which may underlie the angiogenic phenotype of VHL-associated tumours.
Abstract: Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.
4,845 citations
TL;DR: An analysis of observational data over the past 40 years shows a dipole mode in the Indian Ocean: a pattern of internal variability with anomalously low sea surface temperatures off Sumatra and high seasurface temperatures in the western Indian Ocean, with accompanying wind and precipitation anomalies.
Abstract: For the tropical Pacific and Atlantic oceans, internal modes of variability that lead to climatic oscillations have been recognized1,2, but in the Indian Ocean region a similar ocean–atmosphere interaction causing interannual climate variability has not yet been found3. Here we report an analysis of observational data over the past 40 years, showing a dipole mode in the Indian Ocean: a pattern of internal variability with anomalously low sea surface temperatures off Sumatra and high sea surface temperatures in the western Indian Ocean, with accompanying wind and precipitation anomalies. The spatio-temporal links between sea surface temperatures and winds reveal a strong coupling through the precipitation field and ocean dynamics. This air–sea interaction process is unique and inherent in the Indian Ocean, and is shown to be independent of the El Nino/Southern Oscillation. The discovery of this dipole mode that accounts for about 12% of the sea surface temperature variability in the Indian Ocean—and, in its active years, also causes severe rainfall in eastern Africa and droughts in Indonesia—brightens the prospects for a long-term forecast of rainfall anomalies in the affected countries.
4,385 citations
TL;DR: In this article, the authors used thin-film, field effect transistor structures to probe the transport properties of the ordered microcrystalline domains in the conjugated polymer poly(3-hexylthiophene), P3HT.
Abstract: Self-organization in many solution-processed, semiconducting conjugated polymers results in complex microstructures, in which ordered microcrystalline domains are embedded in an amorphous matrix1. This has important consequences for electrical properties of these materials: charge transport is usually limited by the most difficult hopping processes and is therefore dominated by the disordered matrix, resulting in low charge-carrier mobilities2 (⩽10-5 cm2 V-1 s-1). Here we use thin-film, field-effect transistor structures to probe the transport properties of the ordered microcrystalline domains in the conjugated polymer poly(3-hexylthiophene), P3HT. Self-organization in P3HT results in a lamella structure with two-dimensional conjugated sheets formed by interchain stacking. We find that, depending on processing conditions, the lamellae can adopt two different orientations—parallel and normal to the substrate—the mobilities of which differ by more than a factor of 100, and can reach values as high as 0.1 cm2 V-1 s-1 (refs 3, 4). Optical spectroscopy of the field-induced charge, combined with the mobility anisotropy, reveals the two-dimensional interchain character of the polaronic charge carriers, which exhibit lower relaxation energies than the corresponding radical cations on isolated one-dimensional chains. The possibility of achieving high mobilities via two-dimensional transport in self-organized conjugated lamellae is important for applications of polymer transistors in logic circuits5 and active-matrix displays4,6.
4,306 citations
TL;DR: The combination of these phylogenies with powerful new statistical approaches for the analysis of biological evolution is challenging widely held beliefs about the history and evolution of life on Earth.
Abstract: Phylogenetic trees describe the pattern of descent amongst a group of species. With the rapid accumulation of DNA sequence data, more and more phylogenies are being constructed based upon sequence comparisons. The combination of these phylogenies with powerful new statistical approaches for the analysis of biological evolution is challenging widely held beliefs about the history and evolution of life on Earth.
4,159 citations
TL;DR: The World-Wide Web becomes a large directed graph whose vertices are documents and whose edges are links that point from one document to another, which determines the web's connectivity and consequently how effectively the authors can locate information on it.
Abstract: Despite its increasing role in communication, the World-Wide Web remains uncontrolled: any individual or institution can create a website with any number of documents and links. This unregulated growth leads to a huge and complex web, which becomes a large directed graph whose vertices are documents and whose edges are links (URLs) that point from one document to another. The topology of this graph determines the web's connectivity and consequently how effectively we can locate information on it. But its enormous size (estimated to be at least 8×108 documents1) and the continual changing of documents and links make it impossible to catalogue all the vertices and edges.
TL;DR: The identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei is reported, indicating that AIF is a mitochondrial effector of apoptotic cell death.
Abstract: Mitochondria play a key part in the regulation of apoptosis (cell death). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis. Here we report the identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death.
TL;DR: General principles that govern the structure and behaviour of modules may be discovered with help from synthetic sciences such as engineering and computer science, from stronger interactions between experiment and theory in cell biology, and from an appreciation of evolutionary constraints.
Abstract: Cellular functions, such as signal transmission, are carried out by 'modules' made up of many species of interacting molecules Understanding how modules work has depended on combining phenomenological analysis with molecular studies General principles that govern the structure and behaviour of modules may be discovered with help from synthetic sciences such as engineering and computer science, from stronger interactions between experiment and theory in cell biology, and from an appreciation of evolutionary constraints
TL;DR: It is demonstrated that the serine/threonine protein kinase Akt/PKB mediates the activation of eNOS, leading to increased NO production, and represents a novel Ca2+-independent regulatory mechanism for activation ofeNOS.
Abstract: Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is a fundamental determinant of cardiovascular homesotasis: it regulates systemic blood pressure, vascular remodelling and angiogenesis. Physiologically, the most important stimulus for the continuous formation of NO is the viscous drag (shear stress) generated by the streaming blood on the endothelial layer. Although shear-stress-mediated phosphorylation of eNOS is thought to regulate enzyme activity, the mechanism of activation of eNOS is not yet known. Here we demonstrate that the serine/threonine protein kinase Akt/PKB mediates the activation of eNOS, leading to increased NO production. Inhibition of the phosphatidylinositol-3-OH kinase/Akt pathway or mutation of the Akt site on eNOS protein (at serine 1177) attenuates the serine phosphorylation and prevents the activation of eNOS. Mimicking the phosphorylation of Ser 1177 directly enhances enzyme activity and alters the sensitivity of the enzyme to Ca2+, rendering its activity maximal at sub-physiological concentrations of Ca2+. Thus, phosphorylation of eNOS by Akt represents a novel Ca2+-independent regulatory mechanism for activation of eNOS.
TL;DR: It is shown that β-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation.
Abstract: Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene occur in most human colon cancers. Loss of functional APC protein results in the accumulation of beta-catenin. Mutant forms of beta-catenin have been discovered in colon cancers that retain wild-type APC genes, and also in melanomas, medulloblastomas, prostate cancer and gastric and hepatocellular carcinomas. The accumulation of beta-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which beta-catenin interacts. Here we show that beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21ras further activates transcription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant beta-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively. Furthermore, expression of a dominant-negative form of TCF in colon-cancer cells strongly inhibits expression of cyclin D1 without affecting expression of cyclin D2, cyclin E, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cycle; this phenotype can be rescued by expression of cyclin D1 under the cytomegalovirus promoter. Abnormal levels of beta-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.
TL;DR: In this paper, an experimental demonstration of electromagnetically induced transparency in an ultracold gas of sodium atoms, in which the optical pulses propagate at twenty million times slower than the speed of light in a vacuum, is presented.
Abstract: Techniques that use quantum interference effects are being actively investigated to manipulate the optical properties of quantum systems1. One such example is electromagnetically induced transparency, a quantum effect that permits the propagation of light pulses through an otherwise opaque medium2,3,4,5. Here we report an experimental demonstration of electromagnetically induced transparency in an ultracold gas of sodium atoms, in which the optical pulses propagate at twenty million times slower than the speed of light in a vacuum. The gas is cooled to nanokelvin temperatures by laser and evaporative cooling6,7,8,9,10. The quantum interference controlling the optical properties of the medium is set up by a ‘coupling’ laser beam propagating at a right angle to the pulsed ‘probe’ beam. At nanokelvin temperatures, the variation of refractive index with probe frequency can be made very steep. In conjunction with the high atomic density, this results in the exceptionally low light speeds observed. By cooling the cloud below the transition temperature for Bose–Einstein condensation11,12,13 (causing a macroscopic population of alkali atoms in the quantum ground state of the confining potential), we observe even lower pulse propagation velocities (17?m?s−1) owing to the increased atom density. We report an inferred nonlinear refractive index of 0.18?cm2?W−1 and find that the system shows exceptionally large optical nonlinearities, which are of potential fundamental and technological interest for quantum optics.
TL;DR: It is reported that immunization of the young animals essentially prevented the development of β-amyloid-plaque formation, neuritic dystrophy and astrogliosis, and treatment of the older animals markedly reduced the extent and progression of these AD-like neuropathologies.
Abstract: Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.
TL;DR: OPGL is a new regulator of lymph-node organogenesis and lymphocyte development and is an essential osteoclast differentiation factor in vivo.
Abstract: The tumour-necrosis-factor-family molecule osteoprotegerin ligand (OPGL; also known as TRANCE, RANKL and ODF) has been identified as a potential osteoclast differentiation factor and regulator of interactions between T cells and dendritic cells in vitro. Mice with a disrupted opgl gene show severe osteopetrosis and a defect in tooth eruption, and completely lack osteoclasts as a result of an inability of osteoblasts to support osteoclastogenesis. Although dendritic cells appear normal, opgl-deficient mice exhibit defects in early differentiation of T and B lymphocytes. Surprisingly, opgl-deficient mice lack all lymph nodes but have normal splenic structure and Peyer's patches. Thus OPGL is a new regulator of lymph-node organogenesis and lymphocyte development and is an essential osteoclast differentiation factor in vivo.
TL;DR: It is shown that beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma, suggesting that decreased expression of Autophagy proteins may contribute to the development or progression of breast and other human malignancies.
Abstract: The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway, is important in normal growth control and may be defective in tumour cells. However, little is known about the genetic mediators of autophagy in mammalian cells or their role in tumour development. The mammalian gene encoding Beclin 1, a novel Bcl-2-interacting, coiled-coil protein, has structural similarity to the yeast autophagy gene, apg6/vps30, and is mono-allelically deleted in 40-75% of sporadic human breast cancers and ovarian cancers. Here we show, using gene-transfer techniques, that beclin 1 promotes autophagy in autophagy-defective yeast with a targeted disruption of agp6/vps30, and in human MCF7 breast carcinoma cells. The autophagy-promoting activity of beclin 1 in MCF7 cells is associated with inhibition of MCF7 cellular proliferation, in vitro clonigenicity and tumorigenesis in nude mice. Furthermore, endogenous Beclin 1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissue, but is expressed ubiquitously at high levels in normal breast epithelia. Thus, beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma. These findings suggest that decreased expression of autophagy proteins may contribute to the development or progression of breast and other human malignancies.
TL;DR: The cloning of perk is described, a gene encoding a type I transmembrane ER-resident protein that contains a protein-kinase domain most similar to that of the known eIF2α kinases, PKR and HRI that implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.
Abstract: Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER). Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Ire1, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2alpha kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.
TL;DR: It is shown that the serine/threonine protein kinase Akt (protein kinase B) can directly phosphorylate eNOS on serine 1179 and activate the enzyme, leading to NO production, whereas mutant eN OS (S1179A) is resistant to phosphorylation and activation by Akt.
Abstract: Endothelial nitric oxide synthase (eNOS) is the nitric oxide synthase isoform responsible for maintaining systemic blood pressure, vascular remodelling and angiogenesis. eNOS is phosphorylated in response to various forms of cellular stimulation, but the role of phosphorylation in the regulation of nitric oxide (NO) production and the kinase(s) responsible are not known. Here we show that the serine/threonine protein kinase Akt (protein kinase B) can directly phosphorylate eNOS on serine 1179 and activate the enzyme, leading to NO production, whereas mutant eNOS (S1179A) is resistant to phosphorylation and activation by Akt. Moreover, using adenovirus-mediated gene transfer, activated Akt increases basal NO release from endothelial cells, and activation-deficient Akt attenuates NO production stimulated by vascular endothelial growth factor. Thus, eNOS is a newly described Akt substrate linking signal transduction by Akt to the release of the gaseous second messenger NO.
TL;DR: It is shown that the ectopic expression of the telomerase catalytic subunit (hTERT) in combination with two oncogenes results in direct tumorigenic conversion of normal human epithelial and fibroblast cells.
Abstract: During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation. Primary rodent cells are efficiently converted into tumorigenic cells by the coexpression of cooperating oncogenes1,2. However, similar experiments with human cells have consistently failed to yield tumorigenic transformants3,4,5, indicating a fundamental difference in the biology of human and rodent cells. The few reported successes in the creation of human tumour cells have depended on the use of chemical or physical agents to achieve immortalization6, the selection of rare, spontaneously arising immortalized cells7,8,9,10, or the use of an entire viral genome11. We show here that the ectopic expression of the telomerase catalytic subunit (hTERT)12 in combination with two oncogenes (the simian virus 40 large-T oncoprotein and an oncogenic allele of H-ras) results in direct tumorigenic conversion of normal human epithelial and fibroblast cells. These results demonstrate that disruption of the intracellular pathways regulated by large-T, oncogenic ras and telomerase suffices to create a human tumor cell.
TL;DR: The results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.
Abstract: During transduction of an apoptotic (death) signal into the cell, there is an alteration in the permeability of the membranes of the cell's mitochondria, which causes the translocation of the apoptogenic protein cytochrome c into the cytoplasm, which in turn activates death-driving proteolytic proteins known as caspases1,2 The Bcl-2 family of proteins, whose members may be anti-apoptotic or pro-apoptotic, regulates cell death by controlling this mitochondrial membrane permeability during apoptosis3,4,5, but how that is achieved is unclear Here we create liposomes that carry the mitochondrial porin channel (also called the voltage-dependent anion channel, or VDAC) to show that the recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC, whereas the anti-apoptotic protein Bcl-xL closes VDAC by binding to it directly Bax and Bak allow cytochrome c to pass through VDAC out of liposomes, but passage is prevented by Bcl-xL In agreement with this, VDAC1-deficient mitochondria from a mutant yeast did not exhibit a Bax/Bak-induced loss in membrane potential and cytochrome c release, both of which were inhibited by Bcl-xL Our results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis
TL;DR: It is reported that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development, and results indicate that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelialDevelopment and morphogenesis.
Abstract: The p63 gene, a homologue of the tumour-suppressor p53, is highly expressed in the basal or progenitor layers of many epithelial tissues. Here we report that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches and epidermal appendages, which are all sites of reciprocal signalling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge, a stratified epithelium, essential for limb development. The embryonic epidermis of p63-/- mice undergoes an unusual process of non-regenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrymal and salivary glands. Taken together, our results indicate that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis.
TL;DR: It is shown that the Akt serine–threonine kinase is involved in the activation of NF-κB by tumour necrosis factor (TNF), and that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.
Abstract: Activation of the nuclear transcription factor NF-kappaB by inflammatory cytokines requires the successive action of NF-kappaB-inducing kinase (NIK) and an IKB-kinase (IKK) complex composed of IKKalpha and IKKbeta. Here we show that the Akt serine-threonine kinase is involved in the activation of NF-kappaB by tumour necrosis factor (TNF). TNF activates phosphatidylinositol-3-OH kinase (PI(3)K) and its downstream target Akt (protein kinase B). Wortmannin (a PI(3)K inhibitor), dominant-negative PI(3)K or kinase-dead Akt inhibits TNF-mediated NF-kappaB activation. Constitutively active Akt induces NF-kappaB activity and this effect is blocked by dominant-negative NIK. Conversely, NIK activates NF-kappaB and this is blocked by kinase-dead Akt. Thus, both Akt and NIK are necessary for TNF activation of NF-kappaB. Akt mediates IKKalpha phosphorylation at threonine 23. Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-kappaB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses.
TL;DR: In this paper, the authors reported the fabrication of all-semiconductor, light-emitting spintronic devices using III-V heterostructures based on gallium arsenide.
Abstract: Conventional electronics is based on the manipulation of electronic charge. An intriguing alternative is the field of ‘spintronics’, wherein the classical manipulation of electronic spin in semiconductor devices gives rise to the possibility of reading and writing non-volatile information through magnetism1,2. Moreover, the ability to preserve coherent spin states in conventional semiconductors3 and quantum dots4 may eventually enable quantum computing in the solid state5,6. Recent studies have shown that optically excited electron spins can retain their coherence over distances exceeding 100 micrometres (ref. 7). But to inject spin-polarized carriers electrically remains a formidable challenge8,9. Here we report the fabrication of all-semiconductor, light-emitting spintronic devices using III–V heterostructures based on gallium arsenide. Electrical spin injection into a non-magnetic semiconductor is achieved (in zero magnetic field) using a p-type ferromagnetic semiconductor10 as the spin polarizer. Spin polarization of the injected holes is determined directly from the polarization of the emitted electroluminescence following the recombination of the holes with the injected (unpolarized) electrons.
TL;DR: In this article, a single-Cooper-pair box with a gate electrode was used to control the coherent quantum state evolution, which modifies the energies of the two charge states non-adiabatically, bringing them into resonance.
Abstract: 5-7 as a candidate for a quantum bit or 'qubit'—the basic component of a quantum computer. Here we report the observation of quantum oscillations in a single- Cooper-pair box. By applying a short voltage pulse via a gate electrode, we can control the coherent quantum state evolution: the pulse modifies the energies of the two charge states non- adiabatically, bringing them into resonance. The resulting state— a superposition of the two charge states—is detected by a tunnelling current through a probe junction. Our results demon- strate electrical coherent control of a qubit in a solid-state
TL;DR: The authors showed that migratory species can respond rapidly to yearly climate variation, and further global warming is predicted to continue for the next 50-100 years, and some migratory animals can respond quickly to climate variation.
Abstract: Mean global temperatures have risen this century, and further warming is predicted to continue for the next 50-100 years(1-3) Some migratory species can respond rapidly to yearly climate variation ...
TL;DR: It is shown that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP), which indicates that the vanilloid receptor may be another molecular target for endogenousAnandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
Abstract: The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
TL;DR: It is reported that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1.
Abstract: Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of gamma-secretase-mediated cleavage of beta-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. A deficiency in presenilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologues in Caenorhabditis elegans indicate that the presenilins may modulate the Notch signalling pathway. Here we report that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1. Moreover, several gamma-secretase inhibitors block this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus the targeting of gamma-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling.