Alterations of nocturnal activity in rats following subchronic oral administration of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline

1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) is neurotoxic when administered to the brain and alters motor behaviour following intraperitoneal administration. We have assessed the long-term effects of oral TaClo administration on nocturnal motor behaviour in rats. Two groups of rats received TaClo orally at a dose of either 0.2 or 0.4 mg/kg twice daily for 7 weeks. The control group was given saline. No change in locomotor activity was observed 4–9 days after the end of the 7-week administration of TaClo. In addition, the spontaneous motor activity was altered dose-dependently 9 months after oral TaClo administration, with an increase in the low-dose TaClo group and a decrease in the high-dose group. Oral administration of TaClo in rats may be useful in investigating the hypothesis that in Parkinson’s disease, an unknown pathogenic factor crossing the intestinal mucosa barrier can induce neurodegenerative processes eventually affecting the entire brain

Optimization in computational systems biology

Optimization aims to make a system or design as effective or functional as possible. Mathematical optimization methods are widely used in engineering, economics and science. This commentary is focused on applications of mathematical optimization in computational systems biology. Examples are given where optimization methods are used for topics ranging from model building and optimal experimental design to metabolic engineering and synthetic biology. Finally, several perspectives for future research are outlined

Developing optimal input design strategies in cancer systems biology with applications to microfluidic device engineering

<p>Abstract</p> <p>Background</p> <p>Mechanistic models are becoming more and more popular in Systems Biology; identification and control of models underlying biochemical pathways of interest in oncology is a primary goal in this field. Unfortunately the scarce availability of data still limits our understanding of the intrinsic characteristics of complex pathologies like cancer: acquiring information for a system understanding of complex reaction networks is time consuming and expensive. Stimulus response experiments (SRE) have been used to gain a deeper insight into the details of biochemical mechanisms underlying cell life and functioning. Optimisation of the input time-profile, however, still remains a major area of research due to the complexity of the problem and its relevance for the task of information retrieval in systems biology-related experiments.</p> <p>Results</p> <p>We have addressed the problem of quantifying the information associated to an experiment using the Fisher Information Matrix and we have proposed an optimal experimental design strategy based on evolutionary algorithm to cope with the problem of information gathering in Systems Biology. On the basis of the theoretical results obtained in the field of control systems theory, we have studied the dynamical properties of the signals to be used in cell stimulation. The results of this study have been used to develop a microfluidic device for the automation of the process of cell stimulation for system identification.</p> <p>Conclusion</p> <p>We have applied the proposed approach to the Epidermal Growth Factor Receptor pathway and we observed that it minimises the amount of parametric uncertainty associated to the identified model. A statistical framework based on Monte-Carlo estimations of the uncertainty ellipsoid confirmed the superiority of optimally designed experiments over canonical inputs. The proposed approach can be easily extended to multiobjective formulations that can also take advantage of identifiability analysis. Moreover, the availability of fully automated microfluidic platforms explicitly developed for the task of biochemical model identification will hopefully reduce the effects of the 'data rich-data poor' paradox in Systems Biology.</p

Transcriptional Regulation of PP2A-Aα Is Mediated by Multiple Factors Including AP-2α, CREB, ETS-1, and SP-1

Protein phosphatases-2A (PP-2A) is a major serine/threonine phosphatase and accounts for more than 50% serine/threonine phosphatase activity in eukaryotes. The holoenzyme of PP-2A consists of the scaffold A subunit, the catalytic C subunit and the regulatory B subunit. The scaffold subunits, PP2A-Aα/β, provide a platform for both C and B subunits to bind, thus playing a crucial role in providing specific PP-2A activity. Mutation of the two genes encoding PP2A-Aα/β leads to carcinogenesis and likely other human diseases. Regulation of these genes by various factors, both extracellular and intracellular, remains largely unknown. In the present study, we have conducted functional dissection of the promoter of the mouse PP2A-Aα gene. Our results demonstrate that the proximal promoter of the mouse PP2A-Aα gene contains numerous cis-elements for the binding of CREB, ETS-1, AP-2α, SP-1 besides the putative TFIIB binding site (BRE) and the downstream promoter element (DPE). Gel mobility shifting assays revealed that CREB, ETS-1, AP-2α, and SP-1 all bind to PP2A-Aα gene promoter. In vitro mutagenesis and reporter gene activity assays reveal that while SP-1 displays negative regulation, CREB, ETS-1 and AP-2Aα all positively regulate the promoter of the PP2A-Aα gene. ChIP assays further confirm that all the above transcription factors participate the regulation of PP2A-Aα gene promoter. Together, our results reveal that multiple transcription factors regulate the PP2A-Aα gene

Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway

Pathogenic microorganisms often have the ability to attach to a surface, building a complex matrix where they colonize to form a biofilm. This cellular superstructure can display increased resistance to antibiotics and cause serious, persistent health problems in humans. Here we describe a high-throughput in vitro screen to identify inhibitors of Acinetobacter baumannii biofilms using a library of natural product extracts derived from marine microbes. Analysis of extracts derived from Streptomyces gandocaensis results in the discovery of three peptidic metabolites (cahuitamycins A–C), with cahuitamycin C being the most effective inhibitor (IC50=14.5 μM). Biosynthesis of cahuitamycin C proceeds via a convergent biosynthetic pathway, with one of the steps apparently being catalysed by an unlinked gene encoding a 6-methylsalicylate synthase. Efforts to assess starter unit diversification through selective mutasynthesis lead to production of unnatural analogues cahuitamycins D and E of increased potency (IC50=8.4 and 10.5 μM).Great Lakes Regional Center of Excellence for Biodefense and Emerging Infectious Diseases/[U54 AI57153]/GLRCE/Estados UnidosArmy Research Office/[W911NF-12-1-0059]/ARO/Estados UnidosNational Institutes of Health/[1R01GM098350]/NIH/Estados UnidosInternational Cooperative Biodiversity Groups-Fogarty International Center/[U01 TW007404]/ICBG/Estados UnidosUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigaciones en Productos Naturales (CIPRONA

The oncologic radiotherapy experience for patients: a poison-drug La experiencia de los pacientes sometidos a radioterapia oncológica: una medicina-veneno A experiência da radioterapia oncológica para os pacientes: um remédio-veneno

The study aimed at understanding the patients' experience with oncologic radiotherapy. The anthropological interpretative approach and the ethnographic method guided the investigation. Ten patients took part in the study. They were of both genders, within the age range from 34 to 80 years old and monitored during radiotherapy treatment. Data were collected through semi-structured interviews, participative observation and medical records. The analysis of the respondents' statements allowed for the identification of the units of meaning: The encounter with radiotherapy, the body as a vehicle for radiotherapy action and alternative healthcare practices that relieved the effects of the treatment. We understand that the oncologic radiotherapy experience meant the need to submit to a therapy with a characteristic of a poison-drug, which causes fear, but was necessary, whether the goal was cure or even cancer survival.<br>El estudio tuvo como objetivo comprender la experiencia de los pacientes sometidos a radioterapia oncológica. El abordaje de la antropología interpretativa y el método etnográfico orientaron la investigación. Los participantes del estudio fueron diez pacientes de ambos sexos, en el intervalo de edad de 34 a 80 años, acompañados durante el tratamiento radioterápico. Los datos fueron recolectados por entrevistas semi-estructuradas, observación de participante y levantamiento en registros. El análisis de los discursos de los informantes posibilitó identificar las unidades de significado: el encuentro con la radioterapia, el cuerpo como vehículo de acción de la radioterapia y las prácticas alternativas de cuidado para aliviar los efectos del tratamiento. Comprendemos que la experiencia de la radioterapia oncológica significó para esos pacientes la necesidad de someterse a una terapéutica con una característica de medicina-veneno que causa temor, sin embargo que era necesaria, si la meta fuese la cura o la sobre vivencia al cáncer.<br>O estudo objetivou compreender a experiência da radioterapia oncológica para os pacientes. A abordagem da antropologia interpretativa e o método etnográfico nortearam a investigação. Foram informantes dez pacientes de ambos os sexos, na faixa etária de 34 a 80 anos, acompanhados durante o tratamento radioterápico. Os dados foram coletados por entrevistas semi-estruturadas, observação participante e levantamento em prontuários. A análise dos discursos dos informantes possibilitou a identificação das unidades de significado: o encontro com a radioterapia, o corpo como veículo de ação da radioterapia e as práticas alternativas de cuidado aliviando os efeitos do tratamento. Compreende-se, aqui, que a experiência da radioterapia oncológica significou para esses pacientes a necessidade de se submeterem a uma terapêutica com característica de remédio-veneno, que causa temor, mas que era necessária se a meta fosse a cura ou mesmo a sobrevivência ao câncer