Showing papers by "University of California, San Diego published in 1997"
TL;DR: New fluorescent indicators for Ca2+ that are genetically encoded without cofactors and are targetable to specific intracellular locations are constructed and dubbed ‘cameleons’.
Abstract: Important Ca2+ signals in the cytosol and organelles are often extremely localized and hard to measure. To overcome this problem we have constructed new fluorescent indicators for Ca2+ that are genetically encoded without cofactors and are targetable to specific intracellular locations. We have dubbed these fluorescent indicators 'cameleons'. They consist of tandem fusions of a blue- or cyan-emitting mutant of the green fluorescent protein (GFP), calmodulin, the calmodulin-binding peptide M13, and an enhanced green- or yellow-emitting GFP. Binding of Ca2+ makes calmodulin wrap around the M13 domain, increasing the fluorescence resonance energy transfer (FRET) between the flanking GFPs. Calmodulin mutations can tune the Ca2+ affinities to measure free Ca2+ concentrations in the range 10(-8) to 10(-2) M. We have visualized free Ca2+ dynamics in the cytosol, nucleus and endoplasmic reticulum of single HeLa cells transfected with complementary DNAs encoding chimaeras bearing appropriate localization signals. Ca2+ concentration in the endoplasmic reticulum of individual cells ranged from 60 to 400 microM at rest, and 1 to 50 microM after Ca2+ mobilization. FRET is also an indicator of the reversible intermolecular association of cyan-GFP-labelled calmodulin with yellow-GFP-labelled M13. Thus FRET between GFP mutants can monitor localized Ca2+ signals and protein heterodimerization in individual live cells.
3,248 citations
TL;DR: This work has shown that regulation by heterodimerization between Jun, Fos and ATF proteins, AP-1 activity is regulated through interactions with specific protein kinases and a variety of transcriptional coactivators, and there has been considerable progress in understanding some of the mechanisms and signaling pathways involved in the regulation of AP.
2,809 citations
TL;DR: IKK turns out to be the long-sought-after protein kinase that mediates the critical regulatory step in NF-κB activation, and phosphorylates IκBs on the sites that trigger their degradation.
Abstract: Nuclear transcription factors of the NF-κB/Rel family are inhibited by IκB proteins, which inactivate NF-κB by trapping it in the cell cytoplasm. Phosphorylation of IκBs marks them out for destruction, thereby relieving their inhibitory effect on NF-κB. A cytokine-activated protein kinase complex, IKK (for IκB kinase), has now been purified that phosphorylates IκBs on the sites that trigger their degradation. A component of IKK was molecularly cloned and identified as a serine kinase. IKK turns out to be the long-sought-after protein kinase that mediates the critical regulatory step in NF-κB activation.
2,115 citations
TL;DR: In this article, the authors showed that activation of patient CD4 lymphocytes with immobilized antibodies to CD3 and CD28 enabled the isolation of virus from six patients despite the suppression of their plasma HIV RNA to fewer than 50 copies per milliliter for up to 2 years.
Abstract: In evaluating current combination drug regimens for treatment of human immunodeficiency virus (HIV) disease, it is important to determine the existence of viral reservoirs. After depletion of CD8 cells from the peripheral blood mononuclear cells (PBMCs) of both patients and normal donors, activation of patient CD4 lymphocytes with immobilized antibodies to CD3 and CD28 enabled the isolation of virus from PBMCs of six patients despite the suppression of their plasma HIV RNA to fewer than 50 copies per milliliter for up to 2 years. Partial sequencing of HIV pol revealed no new drug resistance mutations or discernible evolution, providing evidence for viral latency rather than drug failure.
2,091 citations
Book•
28 Mar 1997TL;DR: In this paper, strategic voting in single-member single-ballot systems and multi-merge electoral systems is discussed. But the authors focus on the problem of coordination failures and dominant parties.
Abstract: List of tables and figures Series editor's preface Preface PART I. INTRODUCTION: 1. Introduction 2. Duverger's propositions PART II. STRATEGIC VOTING: 3. On electoral systems 4. Strategic voting in single-member single-ballot systems 5. Strategic voting in multimember districts 6. Strategic voting in single-member dual-ballot systems 7. Some concluding comments on strategic voting, PART III. STRATEGIC ENTRY: 8. Strategic voting, party labels and entry 9. Rational entry and the conservation of disproportionality: evidence from Japan PART IV. ELECTORAL COORDINATION AT THe SYSTEM LEVEL: 10. Putting the constituencies together 11. Electoral institutions, cleavage structures and the number of parties PART V. COORDINATION FAILURES AND THE DEMOCRATIC PERFORMANCE: 12. Coordination failures and representation 13. Coordination failures and dominant parties 14. Coordination failures and realignments PART VI. CONCLUSION 15. Conclusion Appendices References Subject index Author index.
2,049 citations
TL;DR: The energy landscape theory of protein folding suggests that the most realistic model of a protein is a minimally frustrated heteropolymer with a rugged funnel-like landscape biased toward the native structure.
Abstract: ▪ Abstract The energy landscape theory of protein folding is a statistical description of a protein's potential surface. It assumes that folding occurs through organizing an ensemble of structures rather than through only a few uniquely defined structural intermediates. It suggests that the most realistic model of a protein is a minimally frustrated heteropolymer with a rugged funnel-like landscape biased toward the native structure. This statistical description has been developed using tools from the statistical mechanics of disordered systems, polymers, and phase transitions of finite systems. We review here its analytical background and contrast the phenomena in homopolymers, random heteropolymers, and protein-like heteropolymers that are kinetically and thermodynamically capable of folding. The connection between these statistical concepts and the results of minimalist models used in computer simulations is discussed. The review concludes with a brief discussion of how the theory helps in the interpre...
2,040 citations
TL;DR: In this paper, the authors provide a concise point of departure for researchers and practitioners alike wishing to assess the current state of the art in the control and monitoring of civil engineering structures, and provide a link between structural control and other fields of control theory.
Abstract: This tutorial/survey paper: (1) provides a concise point of departure for researchers and practitioners alike wishing to assess the current state of the art in the control and monitoring of civil engineering structures; and (2) provides a link between structural control and other fields of control theory, pointing out both differences and similarities, and points out where future research and application efforts are likely to prove fruitful. The paper consists of the following sections: section 1 is an introduction; section 2 deals with passive energy dissipation; section 3 deals with active control; section 4 deals with hybrid and semiactive control systems; section 5 discusses sensors for structural control; section 6 deals with smart material systems; section 7 deals with health monitoring and damage detection; and section 8 deals with research needs. An extensive list of references is provided in the references section.
1,883 citations
TL;DR: In most HIV-infected patients with prior antiretroviral therapy, the combination of indinavir, zidovudine, and lamivudine reduces levels of HIV RNA to less than 500 copies per milliliter for as long as one year.
Abstract: Background The new protease inhibitors are potent inhibitors of the human immunodeficiency virus (HIV), and in combination with other antiretroviral drugs they may be able to cause profound and sustained suppression of HIV replication. Methods In this double-blind study, 97 HIV-infected patients who had received zidovudine treatment for at least 6 months and had 50 to 400 CD4 cells per cubic millimeter and at least 20,000 copies of HIV RNA per milliliter were randomly assigned to one of three treatments for up to 52 weeks: 800 mg of indinavir every eight hours; 200 mg of zidovudine every eight hours combined with 150 mg of lamivudine twice daily; or all three drugs. The patients were followed to monitor the occurrence of adverse events and changes in viral load and CD4 cell counts. Results The decrease in HIV RNA over the first 24 weeks was greater in the three-drug group than in the other groups (P<0.001 for each comparison). RNA levels decreased to less than 500 copies per milliliter at week 24 in 28 of...
1,867 citations
TL;DR: A view of the algorithm as a novel optimization method which combines desirable characteristics of both classical optimization and learning-based algorithms is provided and Mathematical results on conditions for uniqueness of sparse solutions are also given.
Abstract: We present a nonparametric algorithm for finding localized energy solutions from limited data. The problem we address is underdetermined, and no prior knowledge of the shape of the region on which the solution is nonzero is assumed. Termed the FOcal Underdetermined System Solver (FOCUSS), the algorithm has two integral parts: a low-resolution initial estimate of the real signal and the iteration process that refines the initial estimate to the final localized energy solution. The iterations are based on weighted norm minimization of the dependent variable with the weights being a function of the preceding iterative solutions. The algorithm is presented as a general estimation tool usable across different applications. A detailed analysis laying the theoretical foundation for the algorithm is given and includes proofs of global and local convergence and a derivation of the rate of convergence. A view of the algorithm as a novel optimization method which combines desirable characteristics of both classical optimization and learning-based algorithms is provided. Mathematical results on conditions for uniqueness of sparse solutions are also given. Applications of the algorithm are illustrated on problems in direction-of-arrival (DOA) estimation and neuromagnetic imaging.
1,864 citations
TL;DR: The molecular cloning and characterization of IKKbeta, a second subunit of the IKK complex, is described, which is 50% identical to IKKalpha and like it contains a kinase domain, a leucine zipper, and a helix-loop-helix.
1,781 citations
TL;DR: In this article, it was shown that LDL modification induced by cells appeared to be a biologically plausible modification of LDL that could account for foam cell formation and the initiation, or at least acceleration, of the atherosclerotic process.
TL;DR: The role of attention was examined in areas V1, V2, and V4 of macaque monkeys with the use of a behavioral paradigm in which attention was directed to one of two stimulus locations and it was found that the cell's response was strongly influenced by which of the two stimuli was attended.
Abstract: Luck, Steven J., Leonardo Chelazzi, Steven A. Hillyard, and Robert Desimone. Neural mechanisms of spatial selective attention in areas V1, V2, and V4 of macaque visual cortex. J. Neurophysiol. 77: ...
TL;DR: It is shown that purified ACTR is a potent histone acetyltransferase and appears to define a distinct evolutionary branch to this recently described family of coactivator complex.
TL;DR: A biosensor has been developed based on induced wavelength shifts in the Fabry-Perot fringes in the visible-light reflection spectrum of appropriately derivatized thin films of porous silicon semiconductors based on Binding of molecules induced changes in the refractive index of the porous silicon.
Abstract: A biosensor has been developed based on induced wavelength shifts in the Fabry-Perot fringes in the visible-light reflection spectrum of appropriately derivatized thin films of porous silicon semiconductors. Binding of molecules induced changes in the refractive index of the porous silicon. The validity and sensitivity of the system are demonstrated for small organic molecules (biotin and digoxigenin), 16-nucleotide DNA oligomers, and proteins (streptavidin and antibodies) at pico- and femtomolar analyte concentrations. The sensor is also highly effective for detecting single and multilayered molecular assemblies.
TL;DR: It is reported here that even low levels of another mutant, G85R, cause motor neuron disease characterized by an extremely rapid clinical progression, without changes in SOD1 activity.
TL;DR: The functionally conserved proteins CBP and p300 act in conjunction with other factors to activate transcription of DNA and a new factor, p/CIP, has been discovered that is present in the cell as a complex with CBP as mentioned in this paper.
Abstract: The functionally conserved proteins CBP and p300 act in conjunction with other factors to activate transcription of DNA. A new factor, p/CIP, has been discovered that is present in the cell as a complex with CBP and is required for transcriptional activity of nuclear receptors and other CBP/p300-dependent transcription factors. The highly related nuclear-receptor co-activator protein NCoA-1 is also specifically required for ligand-dependent activation of genes by nuclear receptors. p/CIP, NCoA-1 and CBP all contain related leucine-rich charged helical interaction motifs that are required for receptor-specific mechanisms of gene activation, and allow the selective inhibition of distinct signal-transduction pathways.
Brown University1, Harvard University2, International AIDS Society3, Stanford University4, University of British Columbia5, University of California, San Diego6, University of Alabama at Birmingham7, University of Colorado Denver8, Istituto Superiore di Sanità9, University of Paris10, University of California, San Francisco11
TL;DR: Accumulating data from clinical and pathogenesis studies continue to support early institution of potent antiretroviral therapy in patients with HIV infection, and increased complexity in HIV management requires ongoing monitoring of new data for optimal treatment of HIV infection.
Abstract: Objective. —To provide current recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease. Participants. —The original International AIDS Society—USA 13-member panel representing international expertise in antiretroviral research and care of patients with HIV infection. Evidence. —The following were considered: Newly available clinical and basic science study results, including phase 3 controlled trials; clinical, virological, and immunologic end-point data; interim analyses of studies presented at national and international research conferences; studies of HIV pathophysiology; and expert opinions of panel members. Recommendations were limited to the drugs available in mid 1997. Process. —The full panel met on a regular basis (July 1996, September 1996, November 1996, January 1997, and April 1997) since the publication of its initial recommendations in mid 1996 to review new research reports and interim results. The panel discussed whether and how new information changed its initial recommendations. The recommendations contained herein were determined by group consensus. Conclusions. —New data have provided a stronger rationale for earlier initiation of more aggressive therapy than previously recommended and reinforce the importance of careful selection of initial drug regimen for each patient for optimal long-term clinical benefit and adherence. The plasma viral load is a crucial element of clinical management for assessing prognosis and the effectiveness of therapy, and such testing must be done properly. Treatment failure is most readily indicated by a rising plasma HIV RNA level and should be confirmed prior to a change of treatment. Therapeutic approaches must be updated as new data, particularly on the long-term clinical effect of aggressive antiretroviral treatment, continue to emerge.
TL;DR: A study of the photophysical behaviour of single molecules of the green fluorescent protein (GFP) derived from the jellyfish Aequorea victoria suggests the possibility of using these GFPs as fluorescent markers for time-dependent cell processes, and as molecular photonic switches or optical storage elements, addressable on the single-molecule level.
Abstract: Optical studies of individual molecules at low and room temperature can provide information about the dynamics of local environments in solids, liquids and biological systems unobscured by ensemble averaging. Here we present a study of the photophysical behaviour of single molecules of the green fluorescent protein (GFP) derived from the jellyfish Aequorea victoria. Wild-type GFP and its mutant have attracted interest as fluorescent biological labels because the fluorophore may be formed in vivo. GFP mutants immobilized in aereated aqueous polymer gels and excited by 488-nm light undergo repeated cycles of fluorescent emission ('blinking') on a timescale of several seconds-behaviour that would be unobservable in bulk studies. Eventually the individual GFP molecules reach a long-lasting dark state, from which they can be switched back to the original emissive state by irradiation at 405 nm. This suggests the possibility of using these GFPs as fluorescent markers for time-dependent cell processes, and as molecular photonic switches or optical storage elements, addressable on the single-molecule level.
TL;DR: A convergence of repression pathways for bHLH-Zip proteins and nuclear receptors is established and suggests this type of regulation may be more widely conserved than previously suspected.
TL;DR: Data predict that the ligand-induced switch of heterodimeric nuclear receptors from repressor to activator functions involves the exchange of complexes containing histone deacetylases with those that have histone acetylase activity.
Abstract: Transcriptional repression by nuclear receptors has been correlated to binding of the putative co-repressor, N-CoR. A complex has been identified that contains N-CoR, the Mad presumptive co-repressor mSin3, and the histone deacetylase mRPD3, and which is required for both nuclear receptor- and Mad-dependent repression, but not for repression by transcription factors of the ets-domain family. These data predict that the ligand-induced switch of heterodimeric nuclear receptors from repressor to activator functions involves the exchange of complexes containing histone deacetylases with those that have histone acetylase activity.
TL;DR: Findings from this study may be useful for elucidating the in vivo role of growth factors in neurogenesis in the adult CNS and may aid development of neuronal replacement strategies after brain damage.
Abstract: Neurons and glia are generated throughout adulthood from proliferating cells in two regions of the rat brain, the subventricular zone (SVZ) and the hippocampus. This study shows that exogenous basic fibroblast growth factor (FGF-2) and epidermal growth factor (EGF) have differential and site-specific effects on progenitor cells in vivo. Both growth factors expanded the SVZ progenitor population after 2 weeks of intracerebroventricular administration, but only FGF-2 induced an increase in the number of newborn cells, most prominently neurons, in the olfactory bulb, the normal destination for neuronal progenitors migrating from the SVZ. EGF, on the other hand, reduced the total number of newborn neurons reaching the olfactory bulb and substantially enhanced the generation of astrocytes in the olfactory bulb. Moreover, EGF increased the number of newborn cells in the striatum either by migration of SVZ cells or by stimulation of local progenitor cells. No evidence of neuronal differentiation of newborn striatal cells was found by three-dimensional confocal analysis, although many of these newborn cells were associated closely with striatal neurons. The proliferation of hippocampal progenitors was not affected by either growth factor. However, EGF increased the number of newborn glia and reduced the number of newborn neurons, similar to the effects seen in the olfactory bulb. These findings may be useful for elucidating the in vivo role of growth factors in neurogenesis in the adult CNS and may aid development of neuronal replacement strategies after brain damage.
19 Oct 1997
TL;DR: This work studies notions and schemes for symmetric (ie. private key) encryption in a concrete security framework and gives four different notions of security against chosen plaintext attack, providing both upper and lower bounds, and obtaining tight relations.
Abstract: We study notions and schemes for symmetric (ie. private key) encryption in a concrete security framework. We give four different notions of security against chosen plaintext attack and analyze the concrete complexity of reductions among them, providing both upper and lower bounds, and obtaining tight relations. In this way we classify notions (even though polynomially reducible to each other) as stronger or weaker in terms of concrete security. Next we provide concrete security analyses of methods to encrypt using a block cipher, including the most popular encryption method, CBC. We establish tight bounds (meaning matching upper bounds and attacks) on the success of adversaries as a function of their resources.
TL;DR: Data suggest that BDNF protein produced in adult CNS neurons is polarized primarily along axonal processes and is preferentially stored in terminals within the innervation target.
Abstract: A sensitive immunohistochemical technique was used, along with highly specific affinity-purified antibodies to brain-derived neurotrophic factor (BDNF), to generate a detailed mapping of BDNF immunoreactivity (BDNF-ir) throughout the adult rat CNS. A parallel analysis of sites of BDNF synthesis was performed with in situ hybridization techniques using a cRNA probe to the exon encoding mature rat BDNF protein. These combined data revealed (1) groups of cell bodies containing diffuse BDNF-ir throughout the CNS that were strongly correlated with fields of cells containing BDNF mRNA; (2) varying degrees of BDNF-ir outside of cell bodies, in what appeared to be fibers and/or terminals; and (3) many regions containing extremely heavy BDNF-immunoreactive fiber/terminal labeling that lacked BDNF mRNA (e.g., medial habenula, central nucleus of the amygdala, bed nucleus of stria terminalis, lateral septum, and spinal cord). The latter observation suggested that in these regions BDNF was derived from anterograde axonal transport by afferent systems. In the two cases in which this hypothesis was tested by the elimination of select afferents, BDNF immunostaining was completely eliminated. These data, along with the observation that BDNF-ir was rarely found within dendrites or fibers en passage, suggest that BDNF protein produced in adult CNS neurons is polarized primarily along axonal processes and is preferentially stored in terminals within the innervation target.
TL;DR: Turnout in U.S. voter turnout is especially low, but, measured as percent of voting-age population, it is also relatively low in most other countries as mentioned in this paper.
Abstract: Low voter turnout is a serious democratic problem for five reasons: (1) It means unequal turnout that is systematically biased against less well-to-do citizens. (2) Unequal turnout spells unequal political influence. (3) U.S. voter turnout is especially low, but, measured as percent of voting-age population, it is also relatively low in most other countries. (4) Turnout in midterm, regional, local, and supranational elections—less salient but by no means unimportant elections—tends to be especially poor. (5) Turnout appears to be declining everywhere. The problem of inequality can be solved by institutional mechanisms that maximize turnout. One option is the combination of voter-friendly registration rules, proportional representation, infrequent elections, weekend voting, and holding less salient elections concurrently with the most important national elections. The other option, which can maximize turnout by itself, is compulsory voting. Its advantages far outweigh the normative and practical objections to it.
TL;DR: Noncoding, ISS-enriched plasmid DMAs or ISS oligonucleotides (ISS-ODNs) potently stimulate immune responses to coadministered antigens and should be given to adding noncoding DNA adjuvants to inactivated or subunit viral vaccines that, by themselves, provide only partial protection from infection.
Abstract: An adjuvant role for certain short bacterial immunostimulatory DNA sequences (ISSs) has recently been proposed on the basis of their ability to stimulate T helper-1 (Th1) responses in gene-vaccinated animals. We report here that noncoding, ISS-enriched plasmid DNAs or ISS oligonucleotides (ISS-ODNs) potently stimulate immune responses to coadministered antigens. The ISS-DNAs suppress IgE synthesis, but promote IgG and interferon-gamma (IFN-gamma) production. They furthermore initiate the production of IFN-gamma, IFN-alpha, IFN-beta, and interleukins 12 and 18, all of which foster Th1 responses and enhance cell-mediated immunity. Consideration should be given to adding noncoding DNA adjuvants to inactivated or subunit viral vaccines that, by themselves, provide only partial protection from infection.
TL;DR: Heparin, highly sulfated heparan sulfate, and the polysulfonate pharmaceutical Suramin effectively prevented dengue virus infection of target cells, indicating that the envelope protein-target cell receptor interaction is a critical determinant of infectivity.
Abstract: Dengue virus is a human pathogen that has reemerged as an increasingly important public health threat. We found that the cellular receptor utilized by dengue envelope protein to bind to target cells is a highly sulfated type of heparan sulfate. Heparin, highly sulfated heparan sulfate, and the polysulfonate pharmaceutical Suramin effectively prevented dengue virus infection of target cells, indicating that the envelope protein-target cell receptor interaction is a critical determinant of infectivity. The dengue envelope protein sequence includes two putative glycosaminoglycan-binding motifs at the carboxy terminus; the first could be structurally modeled and formed an unusual extended binding surface of basic amino acids. Similar motifs were also identified in the envelope proteins of other flaviviridae. Developing pharmaceuticals that inhibit target cell binding may be an effective strategy for treating flavivirus infections.
TL;DR: It is demonstrated that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia.
Abstract: To determine whether oxidized LDL enhances atherogenesis by promoting monocyte recruitment into the vascular intima, we investigated whether LDL accumulation and oxidation precede intimal accumulation of monocytes in human fetal aortas (from spontaneous abortions and premature newborns who died within 12 h; fetal age 6.2+/-1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from normocholesterolemic mothers (n = 22), hypercholesterolemic mothers (n = 33), and mothers who were hypercholesterolemic only during pregnancy (n = 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age (R = -0.88, P < 0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones (R = 0.86, P = 0.001), whereas in older fetuses no such correlation existed. Fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia contained significantly more and larger lesions (758,651+/-87,449 and 451,255+/-37,448 micron2 per section, respectively; mean+/-SD) than aortas from normocholesterolemic mothers (61,862+/-9,555 micron2; P < 0.00005). Serial sections of the arch, thoracic, and abdominal aortas were immunostained for recognized markers of atherosclerosis: macrophages, apo B, and two different oxidation-specific epitopes (malondialdehyde- and 4-hydroxynonenal-lysine). Of the atherogenic sites that showed positive immunostaining for at least one of these markers, 58.6% were established lesions containing both macrophage/foam cells and oxidized LDL (OxLDL). 17.3% of all sites contained only native LDL, and 13.3% contained only OxLDL without monocyte/ macrophages. In contrast, only 4.3% of sites contained isolated monocytes in the absence of native or oxidized LDL. In addition, 6.3% of sites contained LDL and macrophages but few oxidation-specific epitopes. These results demonstrate that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia. The fact that in very early lesions LDL and OxLDL are frequently found in the absence of monocyte/macrophages, whereas the opposite is rare, suggests that intimal LDL accumulation and oxidation contributes to monocyte recruitment in vivo.
TL;DR: Protein kinase C has been in the spotlight since the discovery two decades ago that it is activated by the lipid second messenger diacylglycerol, but the regulation and specific roles of its isozymes in defined cellular processes are still under intense investigation.
TL;DR: It is concluded that measures of uncertainty are useful and should always be provided, despite simplistic assumptions about the probabilistic models that underlie them, and if uncertainty is too high, reconstruction should be abandoned.
Abstract: Theories of ecological diversification make predictions about the timing and ordering of character state changes through history. These theories are testable by "reconstructing" ancestor states using phylogenetic trees and measurements of contemporary species. Here we use maximum likelihood to estimate and evaluate the accuracy of ancestor reconstructions. We present likelihoods of discrete ancestor states and derive probability distributions for continuous ancestral traits. The methods are applied to several examples: diets of ancestral Darwin's finches; origin of inquilinism in gall wasps; microhabitat partitioning and body size evolution in scrubwrens; digestive enzyme evolution in artiodactyl mammals; origin of a sexually selected male trait, the sword, in platies and swordtails; and evolution of specialization in Anolis lizards. When changes between discrete character states are rare, the maximum-likelihood results are similar to parsimony estimates. In this case the accuracy of estimates is often high, with the exception of some nodes deep in the tree. If change is frequent then reconstructions are highly uncertain, especially of distant ancestors. Ancestor states for continuous traits are typically highly uncertain. We conclude that measures of uncertainty are useful and should always be provided, despite simplistic assumptions about the probabilistic models that underlie them. If uncertainty is too high, reconstruction should be abandoned in favor of approaches that fit different models of trait evolution to species data and phylogenetic trees, taking into account the range of ancestor states permitted by the data.
Smith College1, Boston University2, University of California, San Diego3, University of Savoy4, University of Illinois at Chicago5, University of New Brunswick6, Claude Bernard University Lyon 17, Icahn School of Medicine at Mount Sinai8, University of Amsterdam9, University of Pennsylvania10, University of Newcastle11, Drexel University12, Laval University13, Duke University14, Fordham University15, McGill University16, University of Waterloo17, University of British Columbia18, University of Bath19, University of Padua20, University of Florence21, University of Michigan22
TL;DR: In this article, the authors describe the progress of an international group of investigators who have commenced a coordinated effort to develop a standardized set of cognitive measures for obsessive-compulsive disorder.