Fields Medallist's Lectures (World Scientific Series in 20th Century Mathematics, 9)

(01 December 2003)

World Scientific Series in 20th Century Mathematics - Vol. 9

FIELDS MEDALLISTS' LECTURES
2nd Edition

edited by Sir Michael Atiyah (University of Edinburgh, UK) & Daniel Iagolnitzer (CEA-Saclay, France)

Although the Fields Medal does not have the same public recognition as the Nobel Prizes, they share a similar intellectual standing. It is restricted to one field — that of mathematics — and an age limit of 40 has become an accepted tradition. Mathematics has in the main been interpreted as pure mathematics, and this is not so unreasonable since major contributions in some applied areas can be (and have been) recognized with Nobel Prizes.

A list of Fields Medallists and their contributions provides a bird's-eye view of mathematics over the past 60 years. It highlights the areas in which, at various times, greatest progress has been made. This volume does not pretend to be comprehensive, nor is it a historical document. On the other hand, it presents contributions from Fields Medallists and so provides a highly interesting and varied picture.

The second edition of Fields Medallists' Lectures features additional contributions from the following Medallists: Kunihiko Kodaira (1954), Richard E Borcherds (1998), William T Gowers (1998), Maxim Kontsevich (1998), Curtis T McMullen (1998) and Vladimir Voevodsky (2002).

On the thermodynamic stability of a charged arginine side chain in a transmembrane helix

PNAS, Vol. 104, No. 12. (20 March 2007), pp. 4943-4948.

Biological membranes consist of bilayer arrangements of lipids forming a hydrophobic core that presents a physical barrier to all polar and charged molecules. This long-held notion has recently been challenged by biological translocon-based experiments that report small apparent free energies to insert charged side chains near the center of a transmembrane (TM) helix. We have carried out fully atomistic simulations to provide the free-energy profile for moving a TM helix containing a protonated Arg side chain across a lipid bilayer. Our results reveal the fundamental thermodynamics governing the stability of charged side chains in membranes and the microscopic interactions involved. Despite local membrane deformations, where large amounts of water and lipid head groups are pulled into the bilayer to interact with Arg, the free-energy barrier is 17 kcal/mol. We provide a rationale for the differences in our microscopic free energies and cell biological experiments using free-energy calculations that indicate that a protonated Arg at the central residue of a TM helix of the Leader peptidase might reside close to the interface and not at the membrane center. Our findings have implications for the gating mechanisms of voltage-gated ion channels, suggesting that movements of protonated Arg residues through the membrane will be prohibited. 10.1073/pnas.0610470104

Figure-ground discrimination by relative movement in the visual system of the fly

Biological Cybernetics, Vol. 46, No. 0. (1 January 1983), pp. 1-30.

A moving object can be separated from its surround on the basis of motion information alone. It has been known for some time that various species and especially the housefly can discriminate relative motion of an object and its background, even when the two have an identical texture. An earlier paper (Reichardt and Poggio, 1979) has analyzed on the basis of behavioural experiments the main features of the algorithm used by the fly to separate figure from ground. This paper (a) proposes the basic structure of a neuronal circuitry possibly underlying the detection of discontinuities in the optical flow by the visual system of the houseflyMusca; (b) compares detailed predictions of the model circuitry with old and new behavioural experiments onMusca (measuring its attempts to fixate an object), and (c) studies the neuronal realization of the model circuitry in terms of electrophysiological recordings from the lobula plate horizontal cells of the blowflyCalliphora.

Co-occurrence Network of Reuters News

(15 Dec 2007)

Networks describe various complex natural systems including social systems. We investigate the social network of co-occurrence in Reuters-21578 corpus, which consists of news articles that appeared in the Reuters newswire in 1987. People are represented as vertices and two persons are connected if they co-occur in the same article. The network has small-world features with power-law degree distribution. The network is disconnected and the component size distribution has power law characteristics. Community detection on a degree-reduced network provides meaningful communities. An edge-reduced network, which contains only the strong ties has a star topology. "Importance" of persons are investigated. The network is the situation in 1987. After 20 years, a better judgment on the importance of the people can be done. A number of ranking algorithms, including Citation count, PageRank, are used to assign ranks to vertices. The ranks given by the algorithms are compared against how well a person is represented in Wikipedia. We find up to medium level Spearman's rank correlations. A noteworthy finding is that PageRank consistently performed worse than the other algorithms. We analyze this further and find reasons.

Context-sensitive data integration and prediction of biological networks

Bioinformatics, Vol. 23, No. 17. (1 September 2007), pp. 2322-2330.

Motivation: Several recent methods have addressed the problem of heterogeneous data integration and network prediction by modeling the noise inherent in high-throughput genomic datasets, which can dramatically improve specificity and sensitivity and allow the robust integration of datasets with heterogeneous properties. However, experimental technologies capture different biological processes with varying degrees of success, and thus, each source of genomic data can vary in relevance depending on the biological process one is interested in predicting. Accounting for this variation can significantly improve network prediction, but to our knowledge, no previous approaches have explicitly leveraged this critical information about biological context. Results: We confirm the presence of context-dependent variation in functional genomic data and propose a Bayesian approach for context-sensitive integration and query-based recovery of biological process-specific networks. By applying this method to Saccharomyces cerevisiae, we demonstrate that leveraging contextual information can significantly improve the precision of network predictions, including assignment for uncharacterized genes. We expect that this general context-sensitive approach can be applied to other organisms and prediction scenarios. Availability: A software implementation of our approach is available on request from the authors. Contact: ogt@genomics.princeton.edu Supplementary information: Supplementary data are available at http://avis.princeton.edu/contextPIXIE/ 10.1093/bioinformatics/btm332

Distribution of Amino Acids in a Lipid Bilayer from Computer Simulations

Biophys. J., Vol. 94, No. 9. (1 May 2008), pp. 3393-3404.

We have calculated the distribution in a lipid bilayer of small molecules mimicking 17 natural amino acids in atomistic detail by molecular dynamics simulation. We considered both charged and uncharged forms for Lys, Arg, Glu, and Asp. The results give detailed insight in the molecular basis of the preferred location and orientation of each side chain as well the preferred charge state for ionizable residues. Partitioning of charged and polar side chains is accompanied by water defects connecting the side chains to bulk water. These water defects dominate the energetic of partitioning, rather than simple partitioning between water and a hydrophobic phase. Lys, Glu, and Asp become uncharged well before reaching the center of the membrane, but Arg may be either charged or uncharged at the center of the membrane. Phe has a broad distribution in the membrane but Trp and Tyr localize strongly to the interfacial region. The distributions are useful for the development of coarse-grained and implicit membrane potentials for simulation and structure prediction. We discuss the relationship between the distribution in membranes, bulk partitioning to cyclohexane, and several amino acid hydrophobicity scales. 10.1529/biophysj.107.112805

In Vitro Digestibility of the Cancer-Preventive Soy Peptides Lunasin and BBI

J. Agric. Food Chem., Vol. 55, No. 26. (26 December 2007), pp. 10703-10706.

Abstract: Lunasin and BBI (Bowman Birk protease inhibitor) are bioactive soy peptides that have been shown to be effective suppressors of carcinogenesis in in vitro and in vivo model systems. Since they are subject to digestion in the gastrointestinal tract, we investigated here the stabilities of lunasin and BBI to digestion in vitro by simulated intestinal fluid (SIF) and simulated gastric fluid (SGF). Samples containing lunasin and BBI of varying purities were subjected to in vitro digestion by SIF and SGF at different times and analyzed by Western blot. While the pure BBI reaction is stable after SIF and SGF digestions, the purified lunasin from soybean and synthetic lunasin are easily digested after 2 min in both in vitro digestions. In contrast, lunasin from soy protein containing BBI is comparatively stable after SIF and SGF digestions. Both lunasin and BBI are able to internalize into the cell and localize in the nucleus even after digestion, suggesting that some of the peptides are intact and bioactive. These data suggest that BBI plays a role in protecting lunasin from digestion when soy protein is consumed orally. The role of other soy protease inhibitors such as Kunitz Trypsin Inhibitor (KTI) cannot be excluded from these experiments. Keywords: Lunasin; BBI; in vitro digestibility; SIF; SGF digestion.

Temporal and Anatomic Risk Profile of Brain Injury With Neonatal Repair of Congenital Heart Defects

Stroke, Vol. 38, No. 2. (1 February 2007), pp. 736-741.

Background and Purpose-- Brain injury is common in newborns with congenital heart disease (CHD) requiring neonatal surgery. The purpose of this study is to define the risk factors for preoperative and postoperative brain injuries and their association with functional cardiac anatomic groups. Methods-- Sixty-two neonates with CHD were studied with preoperative MRI, and 53 received postoperative scans. Clinical and therapeutic characteristics were compared in newborns with and without newly acquired brain injuries. A subset of 16 consecutive patients was monitored with intraoperative cerebral near-infrared spectroscopy. Results-- Brain injury was observed in 56% of patients. Preoperative brain injury, seen in 39%, was most commonly stroke and was associated with balloon atrial septostomy (P=0.002). Postoperative brain injury, seen in 35%, was most commonly white matter injury and was particularly common in neonates with single-ventricle physiology and aortic arch obstruction (P=0.001). Risk factors associated with acquired postoperative brain injury included cardiopulmonary bypass (CPB) with regional cerebral perfusion (P=0.01) and lower intraoperative cerebral hemoglobin oxygen saturation during the myocardial ischemic period of CPB (P=0.008). In a multivariable model, new postoperative white matter injury was specifically associated with low mean blood pressure during the first postoperative day (P=0.04). Conclusions-- Specific modifiable risk factors can be identified for preoperative and postoperative white matter injury and stroke associated with neonatal surgery for CHD. The high incidence of postoperative injury observed despite new methodologies of CPB indicates the need for ongoing evaluation to optimize neurological outcome. 10.1161/01.STR.0000247941.41234.90

Near infrared spectroscopy (NIRS) distinguishes seizure types

Seizure, Vol. 9, No. 5. (July 2000), pp. 323-327.

Near infrared spectroscopy (NIRS) is a noninvasive method for bedside measurement of cerebral oxygenation (SaO2). The purpose of this study was to establish differences inSaO2 for complex partial seizures (CPS) and rapidly secondarily generalized CPS (RCPS). We studied eight adults with medically refractory epilepsy undergoing evaluation for temporal lobectomy. We continually measured cerebral SaO2via a Somanetic Invos 3100a cerebral oximeter, pre-ictal (5 minutes), ictal, immediate (30 seconds) post-ictal, and late post-ictal (5 minutes after ictus). Seventeen seizures (12 CPS, four RCPS and one subclinical) were recorded in eight patients. The percentage change in cerebral SaO2from pre-ictal to ictal periods was derived. Cerebral SaO2increased (percentage change, mean: 16.6, SD: 13.9) for CPS and decreased (percentage change, mean: 51.1, SD: 18.1) for RCPS. No change in cerebral oximetry was recorded for the subclinical seizure. Post-ictal (immediate and late) increase in cerebral SaO2was seen for 11 of the 17 seizures (nine CPS and two RCPS). Peripheral SaO2rose greater than 93% for all CPS and the subclinical seizure, but decreased between 78 and 84% during RCPS. These results suggest NIRS distinguishes cerebral SaO2patterns between CPS and RCPS. The decrease in peripheral SaO2, however, may account for the decrease in cerebral SaO2seen in generalized seizures.

Relations between Continuous Performance Test performance measures and ADHD behaviors.

Journal of abnormal child psychology, Vol. 31, No. 5. (October 2003), pp. 543-554.

The Conners' Continuous Performance Test (CPT) is a neuropsychological task that has repeatedly been shown to differentiate ADHD from normal groups. Several variables may be derived from the Conners' CPT including errors of omission and commission, mean hit reaction time(RT), mean hit RT standard error, d', and beta. What each CPT parameter actually assesses has largely been based upon clinical assumptions and the face validity of each measure (e.g., omission errors measure inattention, commission errors measure impulsivity). This study attempts to examine relations between various CPT variables and phenotypic behaviors so as to better understand the various CPT variables. An epidemiological sample of 817 children was administered the Conners' CPT. Diagnostic interviews were conducted with parents to determine ADHD symptom profiles for all children. Children diagnosed with ADHD had more variable RTs, made more errors of commission and omission, and demonstrated poorer perceptual sensitivity than nondiagnosed children. Regarding specific symptoms, generalized estimating equations (GEE) and ANCOVAs were conducted to determine specific relationships between the 18 DSM-IV ADHD symptoms and 6 CPT parameters. CPT performance measures demonstrated significant relationships to ADHD symptoms but did not demonstrate symptom domain specificity according to a priori assumptions. Overall performance on the two signal detection measures, d' and beta, was highly related to all ADHD symptoms across symptom domains. Further, increased variability in RTs over time was related to most ADHD symptoms. Finally, it appears that at least 1 CPT variable, mean hit RT, is minimally related to ADHD symptoms as a whole, but does demonstrate some specificity in its link with symptoms of hyperactivity.

Convergence of different versions of the continuous performance test: clinical and scientific implications.

Journal of clinical and experimental neuropsychology : official journal of the International Neuropsychological Society, Vol. 25, No. 2. (April 2003), pp. 283-292.

The Continuous Performance Test has been used for the last 40 years to measure sustained attention or vigilance in many different populations. Different versions of the test have been developed, but little is known about how similar these tests are, and to what extent performance on different versions of these tests overlaps. In order to examine convergence of the different versions of the CPT, three different CPTs were administered in both the Auditory and Visual Sensory Modalities. Subjects were selected from consecutive admissions to adolescent acute care units at a private psychiatric hospital (n=100). Auditory test modalities uniformly elicited poorer performance than visual tests, while each set of task demands consistently elicited differences in performance. Despite the high test-retest reliability of the individual subtests, the average correlation between tests was r=.42, with the average correlation between visual tests at r=.48 and the average correlation between the auditory tests was r=.45. The correlations within task demands across sensory modalities ranged from a low of.37 to a high of.52. Controlling for IQ did not influence the correlations to a substantial degree. These data suggest different versions of the CPT are correlated with each other at a level consistent with construct validity, but that they do not constitute alternate forms of the same test.

Does the Conners' Continuous Performance Test aid in ADHD diagnosis?

Journal of abnormal child psychology, Vol. 28, No. 5. (October 2000), pp. 415-424.

The performance of clinic-referred children aged 6-11 (N = 100) was examined using the Conners' Continuous Performance Test (CPT) and measures of auditory attention (Auditory Continuous Performance Test; ACPT), phonological awareness, visual processing speed, and visual-motor competence. The Conners' CPT overall index was unrelated to measures of visual processing speed or visual-motor competence. Although the Conners' CPT converged with the ACPT, the latter demonstrated age and order effects. Significant variance in Conners' CPT parameters was predicted by phonological awareness measures, suggesting that Reading Disordered (RD) children could be "false positives" on the Conners' CPT. The Conners' CPT overall index, phonological awareness, and visual-motor measures were submitted to a 2 x 2 MANCOVA (ADHD vs. RD, covarying for age and socioeconomic status): a main effect for RD status was found. Children with ADHD did not have higher Conners' CPT scores than did clinical controls; however, children with Reading Disorders did. Phonological measures distinguished RD children from ADHD children and other clinical controls. ADHD children who failed the Conners' CPT were rated by teachers as more hyperactive. Despite the strengths of the Conners' CPT, its utility for differential diagnosis of ADHD is questioned.

Test-retest reliability and practice effects of a rapid screen of mild traumatic brain injury.

Journal of clinical and experimental neuropsychology : official journal of the International Neuropsychological Society, Vol. 27, No. 5. (July 2005), pp. 624-632.

Test-retest reliabilities and practice effects of measures from the Rapid Screen of Concussion (RSC), in addition to the Digit Symbol Substitution Test (Digit Symbol), were examined. Twenty five male participants were tested three times; each testing session scheduled a week apart. The test-retest reliability estimates for most measures were reasonably good, ranging from .79 to .97. An exception was the delayed word recall test, which has had a reliability estimate of .66 for the first retest, and .59 for the second retest. Practice effects were evident from Times 1 to 2 on the sentence comprehension and delayed recall subtests of the RSC, Digit Symbol and a composite score. There was also a practice effect of the same magnitude found from Time 2 to Time 3 on Digit Symbol, delayed recall and the composite score. Statistics on measures for both the first and second retest intervals, with associated practice effects, are presented to enable the calculation of reliable change indices (RCI). The RCI may be used to assess any improvement in cognitive functioning after mild Traumatic Brain Injury.