Spatial genomic heterogeneity within localized, multifocal prostate cancer

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

A 1.2-Å snapshot of the final step of bacterial cell wall biosynthesis

The cell wall imparts structural strength and shape to bacteria. It is made up of polymeric glycan chains with peptide branches that are cross-linked to form the cell wall. The cross-linking reaction, catalyzed by transpeptidases, is the last step in cell wall biosynthesis. These enzymes are members of the family of penicillin-binding proteins, the targets of β-lactam antibiotics. We report herein the structure of a penicillin-binding protein complexed with a cephalosporin designed to probe the mechanism of the cross-linking reaction catalyzed by transpeptidases. The 1.2-Å resolution x-ray structure of this cephalosporin bound to the active site of the bifunctional serine type d-alanyl-d-alanine carboxypeptidase/transpeptidase (EC 3.4.16.4) from Streptomyces sp. strain R61 reveals how the two peptide strands from the polymeric substrates are sequestered in the active site of a transpeptidase. The structure of this complex provides a snapshot of the enzyme and the bound cell wall components poised for the final and critical cross-linking step of cell wall biosynthesis.

A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain

Alterations in sodium channel expression and function have been suggested as a key molecular event underlying the abnormal processing of pain after peripheral nerve or tissue injury. Although the relative contribution of individual sodium channel subtypes to this process is unclear, the biophysical properties of the tetrodotoxin-resistant current, mediated, at least in part, by the sodium channel PN3 (SNS), suggests that it may play a specialized, pathophysiological role in the sustained, repetitive firing of the peripheral neuron after injury. Moreover, this hypothesis is supported by evidence demonstrating that selective “knock-down” of PN3 protein in the dorsal root ganglion with specific antisense oligodeoxynucleotides prevents hyperalgesia and allodynia caused by either chronic nerve or tissue injury. In contrast, knock-down of NaN/SNS2 protein, a sodium channel that may be a second possible candidate for the tetrodotoxin-resistant current, appears to have no effect on nerve injury-induced behavioral responses. These data suggest that relief from chronic inflammatory or neuropathic pain might be achieved by selective blockade or inhibition of PN3 expression. In light of the restricted distribution of PN3 to sensory neurons, such an approach might offer effective pain relief without a significant side-effect liability.

The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers.

Several epidemiologic studies indicate that NAT2-related slow N-acetylation increases bladder cancer risk among workers exposed to aromatic amines, presumably because N-acetylation is important for the detoxification of these compounds. Previously, we showed that NAT2 polymorphisms did not influence bladder cancer risk among Chinese workers exposed exclusively to benzidine (BZ), suggesting that NAT2 N-acetylation is not a critical detoxifying pathway for this aromatic amine. To evaluate the biologic plausibility of this finding, we carried out a cross-sectional study of 33 workers exposed to BZ and 15 unexposed controls in Ahmedabad, India, to evaluate the presence of BZ-related DNA adducts in exfoliated urothelial cells, the excretion pattern of BZ metabolites, and the impact of NAT2 activity on these outcomes. Four DNA adducts were significantly elevated in exposed workers compared to controls; of these, the predominant adduct cochromatographed with a synthetic N-(3'- phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine standard and was the only adduct that was significantly associated with total BZ urinary metabolites (r = 0.68, P < 0.0001). To our knowledge this is the first report to show that BZ forms DNA adducts in exfoliated urothelial cells of exposed humans and that the predominant adduct formed is N-acetylated, supporting the concept that monofunctional acetylation is an activation, rather than a detoxification, step for BZ. However, because almost all BZ-related metabolites measured in the urine of exposed workers were acetylated among slow, as well as rapid, acetylators (mean +/- SD 95 +/- 1.9% vs. 97 +/- 1.6%, respectively) and NAT2 activity did not affect the levels of any DNA adduct measured, it is unlikely that interindividual variation in NAT2 function is relevant for BZ-associated bladder carcinogenesis.

Studies on the effects of salinity and temperature on the commercial shrimp, Penaeus aztecus Ives : with special regard to survival limits, growth, oxygen consumption and ionic regulation /

"March 1974."

A study in the design of an arithmetic element for serial processing in a linear iterative structure /

Vita.

A note on Atrubin's real-time iterative multiplier /

"UIUCDCS-R-74-640"

Illiac III computer system manual : arithmetic units; volume 2 /

Author of vol. 1 is Daniel E. Atkins.

On Multi- Server Queues With Consultation With Main Server

Queueing Theory is the mathematical study of queues or waiting lines. Queues abound in every day life - in computer networks, in tra c islands, in communication of electro-magnetic signals, in telephone exchange, in bank counters, in super market checkouts, in doctor's clinics, in petrol pumps, in o ces where paper works to be processed and many other places. Originated with the published work of A. K. Erlang in 1909 [16] on congestion in telephone tra c, Queueing Theory has grown tremendously in a century. Its wide range applications includes Operations Research, Computer Science, Telecommunications, Tra c Engineering, Reliability Theory, etc.

Neuromorphic model for sound source segregation

While humans can easily segregate and track a speaker's voice in a loud noisy environment, most modern speech recognition systems still perform poorly in loud background noise. The computational principles behind auditory source segregation in humans is not yet fully understood. In this dissertation, we develop a computational model for source segregation inspired by auditory processing in the brain. To support the key principles behind the computational model, we conduct a series of electro-encephalography experiments using both simple tone-based stimuli and more natural speech stimulus. Most source segregation algorithms utilize some form of prior information about the target speaker or use more than one simultaneous recording of the noisy speech mixtures. Other methods develop models on the noise characteristics. Source segregation of simultaneous speech mixtures with a single microphone recording and no knowledge of the target speaker is still a challenge. Using the principle of temporal coherence, we develop a novel computational model that exploits the difference in the temporal evolution of features that belong to different sources to perform unsupervised monaural source segregation. While using no prior information about the target speaker, this method can gracefully incorporate knowledge about the target speaker to further enhance the segregation.Through a series of EEG experiments we collect neurological evidence to support the principle behind the model. Aside from its unusual structure and computational innovations, the proposed model provides testable hypotheses of the physiological mechanisms of the remarkable perceptual ability of humans to segregate acoustic sources, and of its psychophysical manifestations in navigating complex sensory environments. Results from EEG experiments provide further insights into the assumptions behind the model and provide motivation for future single unit studies that can provide more direct evidence for the principle of temporal coherence.

Evaluación de las causas de los eventos adversos o incidentes que afectan la seguridad del paciente, en el hospital central de la policía de enero 2012 a diciembre 2013

TITULO DEL TRABAJO: Evaluación de las causas de los eventos adversos o incidentes que afectan la seguridad del paciente, en el hospital central de la policía de enero 2012 a diciembre 2013. OBJETIVO: Determinar y analizar la causa raíz de los principales factores de riesgo que afectan la seguridad del paciente que puedan ocasionar eventos adversos en la atención de los pacientes, con el uso de la teoría de restricciones TOC en el Hospital Central de la Policía HOCEN. MATERIALES Y METODO: Se realizó una investigación descriptiva de naturaleza mixta – cuantitativa de tipo correlacional, la población es la totalidad de pacientes atendidos en el hospital de la policía entre enero de 2012 a diciembre de 2013, en el cual se presentaron un total de 189 eventos adversos los cuales sirvieron de objeto a esta investigación, la recolección de datos se realizó por medio de tablas de Excel 2010, posterior a esto se exporto la información al software de IBM SPSS Statistics 19 donde se analiza la información arrojando datos descriptivos y tablas de frecuencia. Finalmente haciendo uso de la Teoría de restricciones TOC se identificó la causa raíz para la ocurrencia de eventos adversos y plantear una intervención estratégica que promueva un sistema efectivo de seguridad del paciente en pro de la búsqueda de la mejora continua. RESULTADOS: Se analizaron 189 eventos adversos, de los cuales 89 fueron reportados en el turno de la noche, seguido por el turno de la mañana con 57, el turno tarde con 27, 28 eventos que no registraron horario, el servicio con mayor ocurrencia es el de medicina interna con 25 eventos, y finalmente la caída de pacientes, lo relacionado con medicamentos, nutriciones y accesos vasculares son los eventos con mayor incidencia. CONCLUSIONES: Se pudo concluir que es necesario que los procesos de seguridad del paciente deben tener un lineamiento directo desde la dirección de la organización permitiendo que las mejoras sean de inmediata aplicación, también es importante generar en el personal una actitud de compromiso frente al proceso de mejora, hay que redefinir las políticas institucionales ya que se concluyó por medio de la teoría de restricciones TOC que el principal factor para la ocurrencia de eventos adversos son las multitareas que el personal tiene que realizar en el proceso de atención.