Tosio Kato (1917–1999)

Tosio Kato was born August 25, 1917, in Kanuma City, Tochigi-ken, Japan. His early training was in physics. He obtained a B.S. in 1941 and the degree of Doctor of Science in 1951, both at the University of Tokyo. Between these events he published papers on a variety of subjects, including pair creation by gamma rays, motion of an object in a fluid, and results on spectral theory of operators arising in quantum mechanics. His dissertation was entitled “On the convergence of the perturbation method”. Kato was appointed assistant professor of physics at the University of Tokyo in 1951 and was promoted to professor of physics in 1958. During this time he visited the University of California at Berkeley in 1954–55, New York University in 1955, the National Bureau of Standards in 1955–56, and Berkeley and the California Institute of Technology in 1957–58. He was appointed professor of mathematics at Berkeley in 1962 and taught there until his retirement in 1988. He supervised twenty-one Ph.D. students at Berkeley and three at the University of Tokyo. Kato published over 160 papers and 6 monographs, including his famous book Perturbation Theory for Linear Operators [K66b]. Recognition for his important work included the Norbert Wiener Prize in Applied Mathematics, awarded in 1980 by the AMS and the Society for Industrial and Applied Mathematics. He was particularly well known for his work on Schrödinger equations of nonrelativistic quantum mechanics and his work on the Navier-Stokes and Euler equations of classical fluid mechanics. His activity in the latter area remained at a high level well past retirement and continued until his death on October 2, 1999

Bayesian Inference and Data Augmentation Schemes for Spatial, Spatiotemporal and Multivariate Log-Gaussian Cox Processes in R

Log-Gaussian Cox processes are an important class of models for spatial and spatiotemporal point-pattern data. Delivering robust Bayesian inference for this class of models presents a substantial challenge, since Markov chain Monte Carlo (MCMC) algorithms require careful tuning in order to work well. To address this issue, we describe recent advances in MCMC methods for these models and their implementation in the R package lgcp. Our suite of R functions provides an extensible framework for inferring covariate effects as well as the parameters of the latent field. We also present methods for Bayesian inference in two further classes of model based on the log-Gaussian Cox process. The first of these concerns the case where we wish to fit a point process model to data consisting of event-counts aggregated to a set of spatial regions: we demonstrate how this can be achieved using data-augmentation. The second concerns Bayesian inference for a class of marked-point processes specified via a multivariate log-Gaussian Cox process model. For both of these extensions, we give details of their implementation in R

Precise calculation of transition frequencies of hydrogen and deuterium based on a least-squares analysis

We combine a limited number of accurately measured transition frequencies in hydrogen and deuterium, recent quantum electrodynamics (QED) calculations, and, as an essential additional ingredient, a generalized least-squares analysis, to obtain precise and optimal predictions for hydrogen and deuterium transition frequencies. Some of the predicted transition frequencies have relative uncertainties more than an order of magnitude smaller than that of the g-factor of the electron, which was previously the most accurate prediction of QED.Comment: 4 pages, RevTe

Modeling cancer genomic data in yeast reveals selection against ATM function during tumorigenesis

The DNA damage response (DDR) comprises multiple functions that collectively preserve genomic integrity and suppress tumorigenesis. The Mre11 complex and ATM govern a major axis of the DDR and several lines of evidence implicate that axis in tumor suppression. Components of the Mre11 complex are mutated in approximately five percent of human cancers. Inherited mutations of complex members cause severe chromosome instability syndromes, such as Nijmegen Breakage Syndrome, which is associated with strong predisposition to malignancy. And in mice, Mre11 complex mutations are markedly more susceptible to oncogene- induced carcinogenesis. The complex is integral to all modes of DNA double strand break (DSB) repair and is required for the activation of ATM to effect DNA damage signaling. To understand which functions of the Mre11 complex are important for tumor suppression, we undertook mining of cancer genomic data from the clinical sequencing program at Memorial Sloan Kettering Cancer Center, which includes the Mre11 complex among the 468 genes assessed. Twenty five mutations in MRE11 and RAD50 were modeled in S. cerevisiae and in vitro. The mutations were chosen based on recurrence and conservation between human and yeast. We found that a significant fraction of tumor-borne RAD50 and MRE11 mutations exhibited separation of function phenotypes wherein Tel1/ATM activation was severely impaired while DNA repair functions were mildly or not affected. At the molecular level, the gene products of RAD50 mutations exhibited defects in ATP binding and hydrolysis. The data reflect the importance of Rad50 ATPase activity for Tel1/ATM activation and suggest that inactivation of ATM signaling confers an advantage to burgeoning tumor cells

An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.

To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers

The Interpersonal Style and Complementarity Between Crisis Negotiators and Forensic Inpatients

Previous negotiation research has explored the interaction and communication between crisis negotiators and perpetrators. A crisis negotiator attempts to resolve a critical incident through negotiation with an individual, or group of persons in crisis. The purpose of this study was to establish the interpersonal style of crisis negotiators and complementarity of the interpersonal interaction between them and forensic inpatients. Crisis negotiators, clinical workers and students (n = 90) used the Check List of Interpersonal Transactions-Revised (CLOIT-R) to identify interpersonal style, along with eight vignettes detailing interpersonal styles. Crisis negotiators were most likely to have a friendly interpersonal style compared to the other non-trained groups. Complementarity theory was not exclusively supported as submissive individuals did not show optimistic judgments in working with dominant forensic inpatients and vice versa. Exploratory analysis revealed that dominant crisis negotiators were optimistic in working with forensic inpatients with a dominant interpersonal style. This study provides insight into the area of interpersonal complementarity of crisis negotiators and forensic inpatients. Whilst further research is required, a potential new finding was established, with significant ‘similarity’ found when dominant crisis negotiators are asked to work with dominant forensic inpatients

A marking of the cricothyroid membrane with extended neck returns to correct position after neck manipulation and repositioning

Background: Emergency front of neck airway access by anaesthetists carries a high failure rate and it is recommended to identify the cricothyroid membrane before induction of anaesthesia in patients with a predicted difficult airway. We have investigated whether a marking of the cricothyroid membrane done in the extended neck position remains correct after the patient's neck has been manipulated and subsequently repositioned METHODS: The subject was first placed in the extended head and neck position and had the cricothyroid membrane identified and marked with three methods, palpation, 'laryngeal handshake' and ultrasonography and the distance from the suprasternal notch to the cricothyroid membrane was measured. The subject then moved off the table and sat on a chair and subsequently returned to the extended neck position and examinations were repeated. Results: Skin markings of all 11 subjects lay within the boundaries of the cricothyroid membrane when the subject was repositioned back to the extended neck position and the median difference between the two measurements of the distance from the suprasternal notch was 0 mm (range 0-2 mm). Conclusion: The cricothyroid membrane can be identified and marked with the subject in the extended neck position. Then the patient's position can be changed as needed, for example to the 'sniffing' neck position for conventional intubation. If a front of neck airway access is required during subsequent airway management, the patient can be returned expediently to the extended-neck position, and the marking of the centre of the membrane will still be in the correct place

Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth Factor β Superfamily Type 1 Receptors.

The transforming growth factor β (TGFβ) superfamily includes TGFβ, activins, inhibins, and bone morphogenetic proteins (BMPs). These extracellular ligands have essential roles in normal tissue homeostasis by coordinately regulating cell proliferation, differentiation, and migration. Aberrant signaling of superfamily members, however, is associated with fibrosis as well as tumorigenesis, cancer progression, metastasis, and drug-resistance mechanisms in a variety of cancer subtypes. Given their involvement in human disease, the identification of novel selective inhibitors of TGFβ superfamily receptors is an attractive therapeutic approach. Seven mammalian type 1 receptors have been identified that have context-specific roles depending on the ligand and the complex formation with the type 2 receptor. Here, we characterize the biologic effects of two transforming growth factor β receptor 1 (TGFBR1) kinase inhibitors designed to target TGFβ signaling. AZ12601011 [2-(2-pyridinyl)-4-(1H-pyrrolo[3,2-c]pyridin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine]; structure previously undisclosed] and AZ12799734 [4-({4-[(2,6-dimethyl-3-pyridinyl)oxy]-2-pyridinyl}amino)benzenesulfonamide] (IC50 = 18 and 47 nM, respectively) were more effective inhibitors of TGFβ-induced reporter activity than SB-431542 [4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide] (IC50 = 84 nM) and LY2157299 [4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide monohydrate]] (galunisertib) (IC50 = 380 nM). AZ12601011 inhibited phosphorylation of SMAD2 via the type 1 receptors activin A receptor type 1B (ALK4), TGFBR1, and activin A receptor type 1C (ALK7). AZ12799734, however, is a pan TGF/BMP inhibitor, inhibiting receptor-mediated phosphorylation of SMAD1 by activin A receptor type 1L, bone morphogenetic protein receptor type 1A, and bone morphogenetic protein receptor type 1B and phosphorylation of SMAD2 by ALK4, TGFBR1, and ALK7. AZ12601011 was highly effective at inhibiting basal and TGFβ-induced migration of HaCaT keratinocytes and, furthermore, inhibited tumor growth and metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumor model. These inhibitors provide new reagents for investigating in vitro and in vivo pathogenic processes and the contribution of TGFβ- and BMP-regulated signaling pathways to disease states