Showing papers by "Stony Brook University published in 2000"
TL;DR: It is shown that ‘loss-of-function’ phenotypes can be created in cultured Drosophila cells by transfection with specific double-stranded RNAs, which coincides with a marked reduction in the level of cognate cellular messenger RNAs.
Abstract: In a diverse group of organisms that includes Caenorhabditis elegans, Drosophila, planaria, hydra, trypanosomes, fungi and plants, the introduction of double-stranded RNAs inhibits gene expression in a sequence-specific manner. These responses, called RNA interference or post-transcriptional gene silencing, may provide anti-viral defence, modulate transposition or regulate gene expression. We have taken a biochemical approach towards elucidating the mechanisms underlying this genetic phenomenon. Here we show that 'loss-of-function' phenotypes can be created in cultured Drosophila cells by transfection with specific double-stranded RNAs. This coincides with a marked reduction in the level of cognate cellular messenger RNAs. Extracts of transfected cells contain a nuclease activity that specifically degrades exogenous transcripts homologous to transfected double-stranded RNA. This enzyme contains an essential RNA component. After partial purification, the sequence-specific nuclease co-fractionates with a discrete, approximately 25-nucleotide RNA species which may confer specificity to the enzyme through homology to the substrate mRNAs.
3,208 citations
TL;DR: In this article, the absolute energy positions of conduction and valence band edges were compiled for about 50 each semiconducting metal oxide and metal sulfide minerals, and the relationship between energy levels at mineral semiconductor-electrolyte interfaces and the activities of these minerals as a catalyst or photocatalyst in aqueous redox reactions were reviewed.
Abstract: The absolute energy positions of conduction and valence band edges were compiled for about 50 each semiconducting metal oxide and metal sulfide minerals. The relationships between energy levels at mineral semiconductor-electrolyte interfaces and the activities of these minerals as a catalyst or photocatalyst in aqueous redox reactions are reviewed. The compilation of band edge energies is based on experimental flatband potential data and complementary empirical calculations from electronegativities of constituent elements. Whereas most metal oxide semiconductors have valence band edges 1 to 3 eV below the H2O oxidation potential (relative to absolute vacuum scale), energies for conduction band edges are close to, or lower than, the H2O reduction potential. These oxide minerals are strong photo-oxidation catalysts in aqueous solutions, but are limited in their reducing power. Non-transition metal sulfides generally have higher conduction and valence band edge energies than metal oxides; therefore, valence band holes in non-transition metal sulfides are less oxidizing, but conduction band electrons are exceedingly reducing. Most transition-metal sulfides, however, are characterized by small band gaps (<1 eV) and band edges situated within or close to the H2O stability potentials. Hence, both the oxidizing power of the valence band holes and the reducing power of the conduction band electrons are lower than those of non-transition metal sulfides.
3,145 citations
TL;DR: It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts, and data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.
Abstract: The c-Jun NH2-terminal kinase (JNK) is activated when cells are exposed to ultraviolet (UV) radiation. However, the functional consequence of JNK activation in UV-irradiated cells has not been established. It is shown here that JNK is required for UV-induced apoptosis in primary murine embryonic fibroblasts. Fibroblasts with simultaneous targeted disruptions of all the functional Jnk genes were protected against UV-stimulated apoptosis. The absence of JNK caused a defect in the mitochondrial death signaling pathway, including the failure to release cytochrome c. These data indicate that mitochondria are influenced by proapoptotic signal transduction through the JNK pathway.
1,738 citations
TL;DR: The results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.
Abstract: The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.
1,694 citations
TL;DR: Smad7 is defined as an adaptor in an E3 ubiquitin-ligase complex that targets the TGF beta receptor for degradation, and mutants that interfere with recruitment of Smurf2 to the receptors are compromised in their inhibitory activity.
1,340 citations
Brown University1, Virginia Commonwealth University2, Stony Brook University3, Stanford University4, University of Washington5, University of Arizona6, Cornell University7, Emory University8, University of Texas Medical Branch9, University of Pittsburgh10, University of Texas Southwestern Medical Center11, Rush University Medical Center12
TL;DR: Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone.
Abstract: Background Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain. Methods We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments. Results Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response ...
1,251 citations
TL;DR: The results support Bowlby's hypothesis that individual differences in attachment security can be stable across significant portions of the lifespan and yet remain open to revision in light of experience.
Abstract: Sixty White middle-class infants were seen in the Ainsworth Strange Situation at 12 months of age; 50 of these participants (21 males, 29 females) were recontacted 20 years later and interviewed by using the Berkeley Adult Attachment Interview (AAI). The interviewers were blind to the participants' Strange Situation classifications. Overall, 72% of the infants received the same secure versus insecure attachment classification in early adulthood, K = .44, p < .001. As predicted by attachment theory, negative life events-defined as (1) loss of a parent, (2) parental divorce, (3) life-threatening illness of parent or child (e.g., diabetes, cancer, heart attack), (4) parental psychiatric disorder, and (5) physical or sexual abuse by a family member-were an important factor in change. Forty-four percent (8 of 18) of the infants whose mothers reported negative life events changed attachment classifications from infancy to early adulthood. Only 22% (7 of 32) of the infants whose mothers reported no such events changed classification, p < .05. These results support Bowlby's hypothesis that individual differences in attachment security can be stable across significant portions of the lifespan and yet remain open to revision in light of experience. The task now is to use a variety of research designs, measurement strategies, and study intervals to clarify the mechanisms underlying stability and change.
1,196 citations
01 Dec 2000
TL;DR: Wound angiogenesis appears to be regulated by endothelial cell interaction with the specific three-dimensional ECM environment in the wound space, and mRNA levels of alpha(v)beta3 in human dermal microvascular endothelial cells either plated on fibronectin or overlaid by fibrin gel were higher than in cells plating on collagen or overlaying by collagen gel.
Abstract: During wound healing, angiogenic capillary sprouts invade the fibrin/fibronectin-rich wound clot and within a few days organize into a microvascular network throughout the granulation tissue. As collagen accumulates in the granulation tissue to produce scar, the density of blood vessels diminishes. A dynamic interaction occurs among endothelial cells, angiogenic cytokines, such as FGF, VEGF, TGF-β, angiopoietin, and mast cell tryptase, and the extracellular matrix (ECM) environment. Specific endothelial cell ECM receptors are critical for these morphogenetic changes in blood vessels during wound repair. In particular, αvβ3, the integrin receptor for fibrin and fibronectin, appears to be required for wound angiogenesis: αvβ3 is expressed on the tips of angiogenic capillary sprouts invading the wound clot, and functional inhibitors of αvβ3 transiently inhibit granulation tissue formation. Recent investigations have shown that the wound ECM can regulate angiogenesis in part by modulating integrin receptor expression. mRNA levels of αvβ3 in human dermal microvascular endothelial cells either plated on fibronectin or overlaid by fibrin gel were higher than in cells plated on collagen or overlaid by collagen gel. Wound angiogenesis also appears to be regulated by endothelial cell interaction with the specific three-dimensional ECM environment in the wound space. In an in vitro model of human sprout angiogenesis, three-dimensional fibrin gel, simulating early wound clot, but not collagen gel, simulating late granulation tissue, supported capillary sprout formation. Understanding the molecular mechanisms that regulate wound angiogenesis, particularly how ECM modulates ECM receptor and angiogenic factor requirements, may provide new approaches for treating chronic wounds.
1,162 citations
TL;DR: Three Kv channel-interacting proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 α-subunits are described that may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium.
Abstract: In the brain and heart, rapidly inactivating (A-type) voltage-gated potassium (Kv) currents operate at subthreshold membrane potentials to control the excitability of neurons and cardiac myocytes. Although pore-forming alpha-subunits of the Kv4, or Shal-related, channel family form A-type currents in heterologous cells, these differ significantly from native A-type currents. Here we describe three Kv channel-interacting proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 alpha-subunits. We find that expression of KChIP and Kv4 together reconstitutes several features of native A-type currents by modulating the density, inactivation kinetics and rate of recovery from inactivation of Kv4 channels in heterologous cells. All three KChIPs co-localize and co-immunoprecipitate with brain Kv4 alpha-subunits, and are thus integral components of native Kv4 channel complexes. The KChIPs have four EF-hand-like domains and bind calcium ions. As the activity and density of neuronal A-type currents tightly control responses to excitatory synaptic inputs, these KChIPs may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium.
953 citations
20 Nov 2000
TL;DR: In this article, Braided tensor categories and ribbon categories have been proposed for topological quantum field theory, and modular functors have been used to model the Wess-Zumino-Witten model.
Abstract: Introduction Braided tensor categories Ribbon categories Modular tensor categories 3-dimensional topological quantum field theory Modular functor Moduli spaces and complex modular functor Wess-Zumino-Witten model Bibliography Index Index of notation.
948 citations
10 Apr 2000
TL;DR: A very simple algorithm for the Least Common Ancestors problem is presented, dispelling the frequently held notion that optimal LCA computation is unwieldy and unimplementable.
Abstract: We present a very simple algorithm for the Least Common Ancestors problem. We thus dispel the frequently held notion that optimal LCA computation is unwieldy and unimplementable. Interestingly, this algorithm is a sequentialization of a previously known PRAM algorithm.
TL;DR: The post-translational modification of Notch by Fringe represents a striking example of modulation of a signalling event by differential receptor glycosylation and identifies a mechanism that is likely to be relevant to other signalling pathways.
Abstract: Notch receptors function in highly conserved intercellular signalling pathways that direct cell-fate decisions, proliferation and apoptosis in metazoans. Fringe proteins can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. Here we establish the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific β1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor-like sequence repeats of Notch. We obtained biological evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signalling by using co-culture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila . The post-translational modification of Notch by Fringe represents a striking example of modulation of a signalling event by differential receptor glycosylation and identifies a mechanism that is likely to be relevant to other signalling pathways.
TL;DR: The choice of a biquintic Hermite polynomial as the interpolating function results in accurately reproducing the underlying Helmholtz free energy data in the table, and yields derivatives of the pressure, specific entropy, and specific internal energy which are smooth and continuous.
Abstract: An electron-positron equation of state based on table interpolation of the Helmholtz free energy is developed and analyzed. The interpolation scheme guarantees perfect thermodynamic consistency, independent of the interpolating function. The choice of a biquintic Hermite polynomial as the interpolating function results in accurately reproducing the underlying Helmholtz free energy data in the table, and yields derivatives of the pressure, specific entropy, and specific internal energy which are smooth and continuous. The execution speed—evaluated across several different machine architectures, compiler options, and modes of operation—suggests that the Helmholtz equation of state routine is faster than any of the five equation of state routines surveyed by Timmes & Arnett. When an optimal balance of accuracy, thermodynamic consistency, and speed is desirable then the tabular Helmholtz equation of state is an excellent choice, particularly for multidimensional models of stellar phenomena.
TL;DR: Examples of cross-talk between Ras and Rho GTPases in animal cells are reviewed, which points to the importance of combinatorial activities controlled by these two families in promoting complex biological responses such as cell proliferation, cell transformation, and cell migration.
Marine Biological Laboratory1, Commonwealth Scientific and Industrial Research Organisation2, University of Alaska Fairbanks3, Stony Brook University4, University of California, Berkeley5, University of British Columbia6, University of York7, University of Copenhagen8, University of Maryland, College Park9, American Institute of Biological Sciences10
TL;DR: Schulze et al. as discussed by the authors presented a conceptual framework for interpreting experimental results and predicting effects of global warming on ecosystems, both in the temporal and spatial patterns of change and in how they affect ecosystems.
Abstract: raise global mean temperature over the next century by 1.0–3.5 °C (Houghton et al. 1995, 1996). Ecologists from around the world have begun experiments to investigate the effects of global warming on terrestrial ecosystems, the aspect of global climate change that attracts the most public attention (Woodwell and McKenzie 1995, Walker and Steffen 1999). The effort to understand response to warming builds on a history of investigations of the effects of elevated CO 2 on plants and ecosystems (Koch and Mooney 1996, Schulze et al. 1999). There are important differences, however, between increases in atmospheric CO 2 and temperature change, both in the temporal and spatial patterns of change and in how they affect ecosystems. The scientists involved in temperature change research have had to face new technical and conceptual challenges in designing and interpreting their experiments (Schulze et al. 1999). In this paper we describe these challenges and present a conceptual framework for interpreting experimental results and predicting effects of warming on ecosystems.
TL;DR: Although it is agreed that predator abundance often affects the consumption rate of individual predators, this phenomenon requires more attention.
Abstract: To describe a predator-prey relationship, it is necessary to specify the rate of prey consumption by an average predator. This functional response largely determines dynamic stability, responses to environmental influences and the nature of indirect effects in the food web containing the predator-prey pair. Nevertheless, measurements of functional responses in nature are quite rare. Recently, much work has been devoted to comparing two idealized forms of the functional response: prey dependent and ratio dependent. Although we agree that predator abundance often affects the consumption rate of individual predators, this phenomenon requires more attention. Disagreement remains over which of the two idealized responses serves as a better starting point in building models when data on predator dependence are absent.
TL;DR: Detergent insolubility is an invaluable tool for studying cellular rafts and characterizing their composition and can depend on lipid composition, detergent and temperature.
TL;DR: Optical photometry is presented that shows moderate detections of light in the B- and V-band images, which are inconsistent with the expected absence of flux shortwards of the Lyman α break for a galaxy at z > 5, and consistent with the previous flux measurement.
Abstract: Observations of distant galaxies are important both for understanding how galaxies form and for probing the physical conditions of the Universe at early times. It is, however, very difficult to identify galaxies at redshifts z > 5, because they are so faint and have few spectral characteristics. We previously reported1 the probable identification of a galaxy at z = 6.68, based on one line and an apparent break in the spectrum just shortwards of that, which we interpreted as Lyman α emission and the Lyman α break, where photons with shorter wavelengths are absorbed by the intervening neutral hydrogen gas. Here we present optical photometry that shows moderate detections of light in the B- and V-band images, which are inconsistent with the expected absence of flux shortwards of the Lyman α break for a galaxy at z > 5, and inconsistent with the previous flux measurement. Moreover, the spectral energy distribution for this object cannot readily be fitted by any known galaxy spectral template at any redshift, so the redshift is undetermined.
TL;DR: In this paper, the authors present new ground-based photometry of the galaxy and find that the galaxy exhibits moderate detections of flux in the optical B and V images that are inconsistent with the expected absence of flux at wavelength shortward of the redshifted Lyman-alpha emission line of a galaxy at redshift z>5.
Abstract: Observations of distant galaxies are important both for understanding how galaxies form and for probing the physical conditions of the universe at the earliest epochs. It is, however, extremely difficult to identify galaxies at redshift z>5, because these galaxies are faint and exhibit few spectral features. In a previous work, we presented observations that supported the identification of a galaxy at redshift z = 6.68 in a deep STIS field. Here we present new ground-based photometry of the galaxy. We find that the galaxy exhibits moderate detections of flux in the optical B and V images that are inconsistent with the expected absence of flux at wavelength shortward of the redshifted Lyman-alpha emission line of a galaxy at redshift z>5. In addition, the new broad-band imaging data not only show flux measurements of this galaxy that are incompatible with the previous STIS measurement, but also suggest a peculiar spectral energy distribution that cannot be fit with any galaxy spectral template at any redshift. We therefore conclude that the redshift identification of this galaxy remains undetermined.
Book•
01 Jan 2000TL;DR: In this article, Howard Rachlin argues that the only way to achieve such control and ultimately happiness is through the development of harmonious patterns of behavior, which is called the primrose path.
Abstract: This book proposes a new science of self-control based on the principles of behavioral psychology and economics. Claiming that insight and self-knowledge are insufficient for controlling one's behavior, Howard Rachlin argues that the only way to achieve such control--and ultimately happiness--is through the development of harmonious patterns of behavior.
Most personal problems with self-control arise because people have difficulty delaying immediate gratification for a better future reward. The alcoholic prefers to drink now. If she is feeling good, a drink will make her feel better. If she is feeling bad, a drink will make her feel better. The problem is that drinking will eventually make her feel worse. This sequence--the consistent choice of a highly valued particular act (such as having a drink or a smoke) that leads to a low-valued pattern of acts--is called "the primrose path."
To avoid it, the author presents a strategy of "soft commitment," consisting of the development of valuable patterns of behavior that bridge over individual temptations. He also proposes, from economics, the concept of the substitutability of "positive addictions," such as social activity or exercise, for "negative addictions," such as drug abuse or overeating. Self-control may be seen as the interaction with one's own future self. Howard Rachlin shows that indeed the value of the whole--of one's whole life--is far greater than the sum of the values of its individual parts.
TL;DR: Views on attachment development, attachment representation, and attachment in family and cross-cultural perspective need to be updated in light of empirical research and advances in developmental theory, behavioral biology, and cognitive psychology.
Abstract: The theory of attachment as a secure-base relationship integrates insights about affect, cognition, and behavior in close relationships across age and culture. Empirical successes based on this theory include important discoveries about the nature of infant-caregiver and adult-adult close relationships, the importance of early experience, and about stability and change in individual differences. The task now is to preserve these insights and successes and build on them. To accomplish this, we need to continually examine the logic and coherence of attachment theory and redress errors of emphasis and analysis. Views on attachment development, attachment representation, and attachment in family and cross-cultural perspective need to be updated in light of empirical research and advances in developmental theory, behavioral biology, and cognitive psychology. We also need to challenge the theory by formulating and testing hypotheses which, if not confirmed, would require significant changes to the theory. If we can accomplish these tasks, prospects for important developments in attachment theory and research are greater than ever, as are the prospects for integration with other disciplines.
Stony Brook University1, University of California, Riverside2, University of California, Berkeley3, Environment Canada4, National Research Council5, Washington State University6, United States Environmental Protection Agency7, University of Virginia8, National Center for Atmospheric Research9, University of Wisconsin-Madison10, Desert Research Institute11
TL;DR: The state of the science concerning biosynthesis, transport, and chemical transformation of hydrocarbons emitted by the terrestrial biosphere is reviewed in this paper, where the focus is on isoprene, monoterpenes, and oxygen-ated polyphenes.
Abstract: Nonmethane hydrocarbons are ubiquitous trace atmospheric constituents yet they control the oxidation capacity of the atmosphere. Both anthropogenic and biogenic processes contribute to the release of hydrocarbons to the atmosphere. In this manuscript, the state of the science concerning biosynthesis, transport, and chemical transformation of hydrocarbons emitted by the terrestrial biosphere is reviewed. In particular, the focus is on isoprene, monoterpenes, and oxygen-ated hydrocarbons. The generated science during the last 10 years is reviewed to explain and quantify hydrocarbon emissions from vegetation and to discern impacts of biogenic hydrocarbons on local and regional atmospheric chemistry. Furthermore, the physiological and environmental processes controlling biosynthesis and production of hydrocarbon compounds are reported on. Many advances have been made on measurement and modeling approaches developed to quantify hydrocarbon emissions from leaves and forest ecosystems. A synthesis of the atmospheric chemistry of biogenic hydrocarbons and their role in the formation of oxidants and aerosols is presented. The integration of biogenic hydrocarbon kinetics and atmospheric physics into mathematical modeling systems is examined to assess the contribution of biogenic hydrocarbons to the formation of oxidants and aerosols, thereby allowing us to study their impacts on the earth's climate system and to develop strategies to reduce oxidant precursors in affected regions.
University of Tokyo1, Boston University2, University of Minnesota3, Brookhaven National Laboratory4, University of California, Irvine5, California State University, Dominguez Hills6, George Mason University7, Gifu University8, University of Hawaii at Manoa9, Kobe University10, Kyoto University11, Los Alamos National Laboratory12, Louisiana State University13, University of Maryland, College Park14, Stony Brook University15, Niigata University16, Osaka University17, Seoul National University18, Shizuoka University19, Tohoku University20, Tokai University21, Tokyo Institute of Technology22, University of Warsaw23, University of Washington24
TL;DR: Using data recorded in 1100 live days of the Super-Kamiokande detector, three complementary data samples are used to study the difference in zenith angle distribution due to neutral currents and matter effects and find no evidence favoring sterile neutrinos, and reject the hypothesis at the 99% confidence level.
Abstract: The previously published atmospheric neutrino data did not distinguish whether muon neutrinos were oscillating into tau neutrinos or sterile neutrinos, as both hypotheses fit the data. Using data recorded in 1100 live days of the Super-Kamiokande detector, we use three complementary data samples to study the difference in zenith angle distribution due to neutral currents and matter effects. We find no evidence favoring sterile neutrinos, and reject the hypothesis at the $99%$ confidence level. On the other hand, we find that oscillation between muon and tau neutrinos suffices to explain all the results in hand.
TL;DR: The substrates for YopJ were shown to be highly conserved ubiquitin-like molecules, which are covalently added to numerous regulatory proteins, which exert their pathogenic effect on cells by disrupting this posttranslational modification.
Abstract: Homologs of the Yersinia virulence effector YopJ are found in both plant and animal bacterial pathogens, as well as plant symbionts. These YopJ family members were shown to act as cysteine proteases. The catalytic triad of the protease was required for inhibition of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling in animal cells and for induction of localized cell death in plants. The substrates for YopJ were shown to be highly conserved ubiquitin-like molecules, which are covalently added to numerous regulatory proteins. YopJ family members exert their pathogenic effect on cells by disrupting this posttranslational modification.
TL;DR: Using a newspaper questionnaire, a door-to-door survey, and 3 laboratory experiments, the authors examined a proposed effect of shared participation in novel and arousing activities on experienced relationship quality and predicted correlations of reported shared "exciting" activities and relationship satisfaction plus their predicted mediation by relationship boredom.
Abstract: Using a newspaper questionnaire, a door-to-door survey, and 3 laboratory experiments, the authors examined a proposed effect of shared participation in novel and arousing activities on experienced relationship quality. The questionnaire and survey studies found predicted correlations of reported shared "exciting" activities and relationship satisfaction plus their predicted mediation by relationship boredom. In all 3 experiments, the authors found predicted greater increases in experienced relationship quality from before to after participating together in a 7-min novel and arousing (vs. a more mundane) task. Comparison with a no-activity control showed the effect was due to the novel-arousing task. The same effect was found on ratings of videotaped discussions before and after the experimental task. Finally, all results remained after controlling for relationship social desirability. Results bear on general issues of boredom and excitement in relationships and the role of such processes in understanding the typical early decline of relationship quality after the honeymoon period.
TL;DR: The failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs appear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have been established.
Abstract: Experimental studies performed prior to 1990 led to the widely held belief that matrix metalloproteinases (MMPs) produced by cancer cells are of critical importance in tumor invasion and metastasis. Based on this evidence, the pharmaceutical industry produced several well tolerated, orally active MMP inhibitors (MMPIs) which demonstrated efficacy in mouse cancer models. Phase III clinical trials initiated in 1997-98 using marimastat, prinomastat (AG3340), and BAY 12-9566 alone or in combination with standard chemotherapy in patients with advanced cancers (lung, prostate, pancreas, brain, GI tract) have recently been reported; no clinical efficacy was demonstrated. Bayer and Agouron have discontinued their ongoing Phase III drug trials of MMPIs in advanced cancer. In retrospect, the failure of MMPIs to alter disease progression in metastatic cancer might have been anticipated since MMPs appear to be important in early aspects of cancer progression (local invasion and micrometastasis) and may no longer be required once metastases have been established. Our understanding of MMP pathophysiology in cancer has expanded considerably in the past 10 years. Current views indicate that: (1) most MMPs in tumors are made by stromal cells, not carcinoma cells; (2) cancer cells induce stromal cells to synthesize MMPs using extracellular matrix metalloproteinase inducer (EMMPRIN) and cytokine stimulatory mechanisms; and (3) MMPs promote cell migration and the release of growth factors sequestered in the extracellular matrix. MMPs have a dual function in tumor angiogenesis: MMP-2 and MT1-MMP are required in breaking down basement membrane barriers in the early stage of angiogenesis, while other MMPs are involved in the generation of an angiogenic inhibitor, angiostatin. In spite of considerable recent progress in identifying multiple roles of MMPs in disease, our understanding of MMP function in cancer is far from complete (see Table 1). Based on accumulated data, it is recommended that future MMPI trials focus on: (1) patients with early stage cancer; (2) the use of MMPIs along with chemotherapy; (3) the measurement of MMPs in tumor tissue and blood as a means of identifying patients who are more likely to respond to MMPI therapy; and (4) identification of biomarkers that reflect activation or inhibition of MMPs in vivo.
TL;DR: It is shown that genotoxic stress blocks cell proliferation and induces apoptosis of germ cells in the nematode C. elegans and implicates rad1 homologs in DNA damage-induced apoptosis in animals.
TL;DR: This work is supported by the National Cancer Institute (CA7373501), the Baldwin Foundation for Breast Cancer Research, and the Association for International Cancer Research.
Abstract: X.R.B. is a Sinsheimer Scholar for Cancer Research whose own work is supported by the National Cancer Institute (CA7373501), the Baldwin Foundation for Breast Cancer Research, and the Association for International Cancer Research.
TL;DR: In this article, the authors apply the theory of hyperbolic spaces and groups to algorithmic questions for the Mapping Class Group and geometric properties of Kleinian representations of Harvey's Complex of Curves.
Abstract: This paper continues a geometric study of Harvey's Complex of Curves, whose ultimate goal is to apply the theory of hyperbolic spaces and groups to algorithmic questions for the Mapping Class Group and geometric properties of Kleinian representations. The authors' previous result that the complex is delta-hyperbolic was hard to apply because the complex is not locally finite; in this paper some tools are developed for overcoming this problem, and a combinatorial mechanism introduced which describes sequences of elementary moves in the graph of markings on a surface. These tools are applied to give a family of quasi-geodesic words in the Mapping Class Group, and a linear bound on the shortest word conjugating two conjugate pseudo-Anosov elements.
A basic tool in the analysis is a family of subsurface projections, which are roughly analogous to closest-point projections to horoballs in classical hyperbolic space. These projections have a strong contraction property which makes it possible to tie together the geometry of the complex and that of the (infinite) subcomplexes that arise as links of vertices. The resulting layered structure of the complex is controlled by means of a combinatorial device called a hierarchy of geodesics, which is the central construction of the paper.
TL;DR: The experiments indicate that the effect of sterol on the ability of saturated lipids to form a tightly packed and ordered state is the key to their effect on domain formation.
Abstract: Detergent-insoluble membrane domains, enriched in saturated lipids and cholesterol, have been implicated in numerous biological functions. To understand how cholesterol promotes domain formation, the effect of various sterols and sterol derivatives on domain formation in mixtures of the saturated lipid dipalmitoylphosphatidylcholine (DPPC) and a fluorescence quenching analogue of an unsaturated lipid was compared. Quenching measurements demonstrated that several sterols (cholesterol, dihydrocholesterol, epicholesterol, and 25-hydroxycholesterol) promote formation of DPPC-enriched domains. Other sterols and sterol derivatives had little effect on domain formation (cholestane and lanosterol) or, surprisingly, strongly inhibit it (coprostanol, androstenol, cholesterol sulfate, and 4-cholestenone). The effect of sterols on domain formation was closely correlated with their effects on DPPC insolubility. Those sterols that promoted domain formation increased DPPC insolubility, whereas those sterols that inhibit...