Showing papers by "University of California, San Diego published in 2002"

Shape matching and object recognition using shape contexts

Abstract: We present a novel approach to measuring similarity between shapes and exploit it for object recognition. In our framework, the measurement of similarity is preceded by: (1) solving for correspondences between points on the two shapes; (2) using the correspondences to estimate an aligning transform. In order to solve the correspondence problem, we attach a descriptor, the shape context, to each point. The shape context at a reference point captures the distribution of the remaining points relative to it, thus offering a globally discriminative characterization. Corresponding points on two similar shapes will have similar shape contexts, enabling us to solve for correspondences as an optimal assignment problem. Given the point correspondences, we estimate the transformation that best aligns the two shapes; regularized thin-plate splines provide a flexible class of transformation maps for this purpose. The dissimilarity between the two shapes is computed as a sum of matching errors between corresponding points, together with a term measuring the magnitude of the aligning transform. We treat recognition in a nearest-neighbor classification framework as the problem of finding the stored prototype shape that is maximally similar to that in the image. Results are presented for silhouettes, trademarks, handwritten digits, and the COIL data set.

Initial sequencing and comparative analysis of the mouse genome.

Abstract: The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Dynamic Conditional Correlation: A Simple Class of Multivariate Generalized Autoregressive Conditional Heteroskedasticity Models

Abstract: Time varying correlations are often estimated with multivariate generalized autoregressive conditional heteroskedasticity (GARCH) models that are linear in squares and cross products of the data. A new class of multivariate models called dynamic conditional correlation models is proposed. These have the flexibility of univariate GARCH models coupled with parsimonious parametric models for the correlations. They are not linear but can often be estimated very simply with univariate or two-step methods based on the likelihood function. It is shown that they perform well in a variety of situations and provide sensible empirical results.

Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia

Abstract: Micro-RNAs (miR genes) are a large family of highly conserved noncoding genes thought to be involved in temporal and tissue-specific gene regulation MiRs are transcribed as short hairpin precursors (≈70 nt) and are processed into active 21- to 22-nt RNAs by Dicer, a ribonuclease that recognizes target mRNAs via base-pairing interactions Here we show that miR15 and miR16 are located at chromosome 13q14, a region deleted in more than half of B cell chronic lymphocytic leukemias (B-CLL) Detailed deletion and expression analysis shows that miR15 and miR16 are located within a 30-kb region of loss in CLL, and that both genes are deleted or down-regulated in the majority (≈68%) of CLL cases

A central role for JNK in obesity and insulin resistance

Abstract: Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.

Voriconazole versus Amphotericin B for Primary Therapy of Invasive Aspergillosis

Abstract: Background Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis. Methods In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome. Results A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematop...

SNOPT: An SQP Algorithm for Large-Scale Constrained Optimization

Abstract: Sequential quadratic programming (SQP) methods have proved highly effective for solving constrained optimization problems with smooth nonlinear functions in the objective and constraints. Here we consider problems with general inequality constraints (linear and nonlinear). We assume that first derivatives are available and that the constraint gradients are sparse. We discuss an SQP algorithm that uses a smooth augmented Lagrangian merit function and makes explicit provision for infeasibility in the original problem and the QP subproblems. SNOPT is a particular implementation that makes use of a semidefinite QP solver. It is based on a limited-memory quasi-Newton approximation to the Hessian of the Lagrangian and uses a reduced-Hessian algorithm (SQOPT) for solving the QP subproblems. It is designed for problems with many thousands of constraints and variables but a moderate number of degrees of freedom (say, up to 2000). An important application is to trajectory optimization in the aerospace industry. Numerical results are given for most problems in the CUTE and COPS test collections (about 900 examples).

Optimal feedback control as a theory of motor coordination.

Abstract: A central problem in motor control is understanding how the many biomechanical degrees of freedom are coordinated to achieve a common goal. An especially puzzling aspect of coordination is that behavioral goals are achieved reliably and repeatedly with movements rarely reproducible in their detail. Existing theoretical frameworks emphasize either goal achievement or the richness of motor variability, but fail to reconcile the two. Here we propose an alternative theory based on stochastic optimal feedback control. We show that the optimal strategy in the face of uncertainty is to allow variability in redundant (task-irrelevant) dimensions. This strategy does not enforce a desired trajectory, but uses feedback more intelligently, correcting only those deviations that interfere with task goals. From this framework, task-constrained variability, goal-directed corrections, motor synergies, controlled parameters, simplifying rules and discrete coordination modes emerge naturally. We present experimental results from a range of motor tasks to support this theory.

Molecular dynamics simulations of biomolecules

Abstract: Molecular dynamics simulations are important tools for understanding the physical basis of the structure and function of biological macromolecules. The early view of proteins as relatively rigid structures has been replaced by a dynamic model in which the internal motions and resulting conformational changes play an essential role in their function. This review presents a brief description of the origin and early uses of biomolecular simulations. It then outlines some recent studies that illustrate the utility of such simulations and closes with a discussion of their ever-increasing potential for contributing to biology.

Determination of effective permittivity and permeability of metamaterials from reflection and transmission coefficients

Abstract: We analyze the reflection and transmission coefficients calculated from transfer matrix simulations on finite lengths of electromagnetic metamaterials, to determine the effective permittivity ~«! and permeability ~m! .W e perform this analysis on structures composed of periodic arrangements of wires, split ring resonators ~SRRs!, and both wires and SRRs. We find the recovered frequency-dependent« and m are entirely consistent with analytic expressions predicted by effective medium arguments. Of particular relevance are that a wire medium exhibits a frequency region in which the real part of « is negative, and SRRs produce a frequency region in which the real part of m is negative. In the combination structure, at frequencies where both the recovered real parts of « and m are simultaneously negative, the real part of the index of refraction is also found to be unambiguously negative.

AP-1 as a regulator of cell life and death

Abstract: The transcription factor AP-1 (activator protein-1) is involved in cellular proliferation, transformation and death. Using mice and cells lacking AP-1 components, the target-genes and molecular mechanisms mediating these processes were recently identified. Interestingly, the growth-promoting activity of c-Jun is mediated by repression of tumour suppressors, as well as upregulation of positive cell cycle regulators. Mostly, c-Jun is a positive regulator of cell proliferation, whereas JunB has the converse effect. The intricate relationships between the different Jun proteins, their activities and the mechanisms that mediate them will be discussed.

NF-κB at the crossroads of life and death

Abstract: The choice between life and death is one of the major events in regulation of the immune system. T cells that specifically recognize viral or bacterial antigens are selected to survive and proliferate in response to infection, whereas those that are self-reactive are eliminated via apoptosis. Even the survival of alloreactive T cells requires their proper costimulation and, when infection subsides, the activated T cells are eliminated. A major regulator of such life or death decisions is the transcription factor NF-κB. However, NF-κB cannot function alone. A variety of mechanisms exist to modulate its activity and thereby affect the ultimate outcome of a cell's fate.

A monomeric red fluorescent protein

Abstract: All coelenterate fluorescent proteins cloned to date display some form of quaternary structure, including the weak tendency of Aequorea green fluorescent protein (GFP) to dimerize, the obligate dimerization of Renilla GFP, and the obligate tetramerization of the red fluorescent protein from Discosoma (DsRed). Although the weak dimerization of Aequorea GFP has not impeded its acceptance as an indispensable tool of cell biology, the obligate tetramerization of DsRed has greatly hindered its use as a genetically encoded fusion tag. We present here the stepwise evolution of DsRed to a dimer and then either to a genetic fusion of two copies of the protein, i.e., a tandem dimer, or to a true monomer designated mRFP1 (monomeric red fluorescent protein). Each subunit interface was disrupted by insertion of arginines, which initially crippled the resulting protein, but red fluorescence could be rescued by random and directed mutagenesis totaling 17 substitutions in the dimer and 33 in mRFP1. Fusions of the gap junction protein connexin43 to mRFP1 formed fully functional junctions, whereas analogous fusions to the tetramer and dimer failed. Although mRFP1 has somewhat lower extinction coefficient, quantum yield, and photostability than DsRed, mRFP1 matures >10 times faster, so that it shows similar brightness in living cells. In addition, the excitation and emission peaks of mRFP1, 584 and 607 nm, are ≈25 nm red-shifted from DsRed, which should confer greater tissue penetration and spectral separation from autofluorescence and other fluorescent proteins.

Bosentan therapy for pulmonary arterial hypertension.

Abstract: Methods In this double-blind, placebo-controlled study, we randomly assigned 213 patients with pulmonary arterial hypertension (primary or associated with connective-tissue disease) to receive placebo or to receive 62.5 mg of bosentan twice daily for 4 weeks followed by either of two doses of bosentan (125 or 250 mg twice daily) for a minimum of 12 weeks. The primary end point was the degree of change in exercise capacity. Secondary end points included the change in the Borg dyspnea index, the change in the World Health Organization (WHO) functional class, and the time to clinical worsening. Results At week 16, patients treated with bosentan had an improved six-minute walking distance; the mean difference between the placebo group and the combined bosentan groups was 44 m (95 percent confidence interval, 21 to 67; P<0.001). Bosentan also improved the Borg dyspnea index and WHO functional class and increased the time to clinical worsening. Conclusions The endothelin-receptor antagonist bosentan is beneficial in patients with pulmonary arterial hypertension and is well tolerated at a dose of 125 mg twice daily. Endothelin-receptor antagonism with oral bosentan is an effective approach to therapy for pulmonary arterial hypertension. (N Engl J Med

NF-κB in cancer: from innocent bystander to major culprit

Abstract: Nuclear factor of κB (NF-κB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-κB in immunity is undisputed, recent evidence indicates that NF-κB and the signalling pathways that are involved in its activation are also important for tumour development. NF-κB should therefore receive as much attention from cancer researchers as it has already from immunologists.

Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells.

Abstract: Many proteins associated with the plasma membrane are known to partition into submicroscopic sphingolipid- and cholesterol-rich domains called lipid rafts, but the determinants dictating this segregation of proteins in the membrane are poorly understood. We suppressed the tendency of Aequorea fluorescent proteins to dimerize and targeted these variants to the plasma membrane using several different types of lipid anchors. Fluorescence resonance energy transfer measurements in living cells revealed that acyl but not prenyl modifications promote clustering in lipid rafts. Thus the nature of the lipid anchor on a protein is sufficient to determine submicroscopic localization within the plasma membrane.

Face recognition by independent component analysis

Abstract: A number of current face recognition algorithms use face representations found by unsupervised statistical methods. Typically these methods find a set of basis images and represent faces as a linear combination of those images. Principal component analysis (PCA) is a popular example of such methods. The basis images found by PCA depend only on pairwise relationships between pixels in the image database. In a task such as face recognition, in which important information may be contained in the high-order relationships among pixels, it seems reasonable to expect that better basis images may be found by methods sensitive to these high-order statistics. Independent component analysis (ICA), a generalization of PCA, is one such method. We used a version of ICA derived from the principle of optimal information transfer through sigmoidal neurons. ICA was performed on face images in the FERET database under two different architectures, one which treated the images as random variables and the pixels as outcomes, and a second which treated the pixels as random variables and the images as outcomes. The first architecture found spatially local basis images for the faces. The second architecture produced a factorial face code. Both ICA representations were superior to representations based on PCA for recognizing faces across days and changes in expression. A classifier that combined the two ICA representations gave the best performance.

The Protein Data Bank.

Abstract: The Protein Data Bank [PDB; Berman, Westbrook et al. (2000), Nucleic Acids Res. 28, 235–242; http://www.pdb.org/] is the single worldwide archive of primary structural data of biological macromolecules. Many secondary sources of information are derived from PDB data. It is the starting point for studies in structural bioinformatics. This article describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information and plans for the future development of the resource. The reader should come away with an understanding of the scope of the PDB and what is provided by the resource.

Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II)

Abstract: 1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall, 0.99 (0.84-1.17). The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women who were adherent to randomized treatment assignment (RH, 0.96; 95% CI, 0.77-1.19). Conclusions Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.

Creating new fluorescent probes for cell biology.

Abstract: Fluorescent probes are one of the cornerstones of real-time imaging of live cells and a powerful tool for cell biologists. They provide high sensitivity and great versatility while minimally perturbing the cell under investigation. Genetically-encoded reporter constructs that are derived from fluorescent proteins are leading a revolution in the real-time visualization and tracking of various cellular events. Recent advances include the continued development of 'passive' markers for the measurement of biomolecule expression and localization in live cells, and 'active' indicators for monitoring more complex cellular processes such as small-molecule-messenger dynamics, enzyme activation and protein-protein interactions.

The long-term natural history of the weekly symptomatic status of bipolar I disorder.

Abstract: Background To our knowledge, this is the first prospective natural history study of weekly symptomatic status of patients with bipolar I disorder (BP-I) during long-term follow-up. Methods Analyses are based on ongoing prospective follow-up of 146 patients with Research Diagnostic Criteria BP-I, who entered the National Institute of Mental Health (Bethesda, Md) Collaborative Depression Study from 1978 through1981. Weekly affective symptom status ratings were analyzed by polarity and severity, ranging from asymptomatic, to subthreshold levels, to full-blown major depression and mania. Percentages of follow-up weeks at each level as well as number of shifts in symptom status and polarity during the entire follow-up period were examined. Finally, 2 new measures of chronicity were evaluated in relation to previously identified predictors of chronicity for BP-I. Results Patients with BP-I were symptomatically ill 47.3% of weeks throughout a mean of 12.8 years of follow-up. Depressive symptoms (31.9% of total follow-up weeks) predominated over manic/hypomanic symptoms (8.9% of weeks) or cycling/mixed symptoms (5.9% of weeks). Subsyndromal, minor depressive, and hypomanic symptoms combined were nearly 3 times more frequent than syndromal-level major depressive and manic symptoms (29.9% vs 11.2% of weeks, respectively). Patients with BP-I changed symptom status an average of 6 times per year and polarity more than 3 times per year. Longer intake episodes and those with depression-only or cycling polarity predicted greater chronicity during long-term follow-up, as did comorbid drug-use disorder. Conclusions The longitudinal weekly symptomatic course of BP-I is chronic. Overall, the symptomatic structure is primarily depressive rather than manic, and subsyndromal and minor affective symptoms predominate. Symptom severity levels fluctuate, often within the same patient over time. Bipolar I disorder is expressed as a dimensional illness featuring the full range (spectrum) of affective symptom severity and polarity.

|[alpha]|-Synuclein is phosphorylated in synucleinopathy lesions

Abstract: The deposition of the abundant presynaptic brain protein alpha-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. However, specific post-translational modifications that underlie the aggregation of alpha-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of alpha-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.

Automatically characterizing large scale program behavior

Abstract: Understanding program behavior is at the foundation of computer architecture and program optimization. Many programs have wildly different behavior on even the very largest of scales (over the complete execution of the program). This realization has ramifications for many architectural and compiler techniques, from thread scheduling, to feedback directed optimizations, to the way programs are simulated. However, in order to take advantage of time-varying behavior, we must first develop the analytical tools necessary to automatically and efficiently analyze program behavior over large sections of execution.Our goal is to develop automatic techniques that are capable of finding and exploiting the Large Scale Behavior of programs (behavior seen over billions of instructions). The first step towards this goal is the development of a hardware independent metric that can concisely summarize the behavior of an arbitrary section of execution in a program. To this end we examine the use of Basic Block Vectors. We quantify the effectiveness of Basic Block Vectors in capturing program behavior across several different architectural metrics, explore the large scale behavior of several programs, and develop a set of algorithms based on clustering capable of analyzing this behavior. We then demonstrate an application of this technology to automatically determine where to simulate for a program to help guide computer architecture research.

Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs

Abstract: Only a small proportion of the mouse genome is transcribed into mature messenger RNA transcripts There is an international collaborative effort to identify all full-length mRNA transcripts from the mouse, and to ensure that each is represented in a physical collection of clones Here we report the manual annotation of 60,770 full-length mouse complementary DNA sequences These are clustered into 33,409 'transcriptional units', contributing 901% of a newly established mouse transcriptome database Of these transcriptional units, 4,258 are new protein-coding and 11,665 are new non-coding messages, indicating that non-coding RNA is a major component of the transcriptome 41% of all transcriptional units showed evidence of alternative splicing In protein-coding transcripts, 79% of splice variations altered the protein product Whole-transcriptome analyses resulted in the identification of 2,431 sense-antisense pairs The present work, completely supported by physical clones, provides the most comprehensive survey of a mammalian transcriptome so far, and is a valuable resource for functional genomics

Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections.

Abstract: The viruses HIV-1, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and hepatitis C virus (HCV) are characterized by the establishment of lifelong infection in the human host, where their replication is thought to be tightly controlled by virus-specific CD8+ T cells. Here we present detailed studies of the differentiation phenotype of these cells, which can be separated into three distinct subsets based on expression of the costimulatory receptors CD28 and CD27. Whereas CD8+ T cells specific for HIV, EBV and HCV exhibit similar characteristics during primary infection, there are significant enrichments at different stages of cellular differentiation in the chronic phase of persistent infection according to the viral specificity, which suggests that distinct memory T-cell populations are established in different virus infections. These findings challenge the current definitions of memory and effector subsets in humans, and suggest that ascribing effector and memory functions to subsets with different differentiation phenotypes is no longer appropriate.

Closest point search in lattices

Abstract: In this semitutorial paper, a comprehensive survey of closest point search methods for lattices without a regular structure is presented. The existing search strategies are described in a unified framework, and differences between them are elucidated. An efficient closest point search algorithm, based on the Schnorr-Euchner (1995) variation of the Pohst (1981) method, is implemented. Given an arbitrary point x /spl isin/ /spl Ropf//sup m/ and a generator matrix for a lattice /spl Lambda/, the algorithm computes the point of /spl Lambda/ that is closest to x. The algorithm is shown to be substantially faster than other known methods, by means of a theoretical comparison with the Kannan (1983, 1987) algorithm and an experimental comparison with the Pohst (1981) algorithm and its variants, such as the Viterbo-Boutros (see ibid. vol.45, p.1639-42, 1999) decoder. Modifications of the algorithm are developed to solve a number of related search problems for lattices, such as finding a shortest vector, determining the kissing number, computing the Voronoi (1908)-relevant vectors, and finding a Korkine-Zolotareff (1873) reduced basis.