Exit times for some processes with normally distributed noise

Denna avhandling handlar om metoder för att hitta begränsningar för det asymptotiska beteendet hos en förväntad uthoppstid från ett område omkring en xpunkt för processer som har normalfördelad störning. I huvudsak behandlas olika typer av autoregressiva processer. Fyra olika metoder används. En metod som använder principen för stora avvikelser samt en metod som jämför uthoppstiden med en återkomsttid ger övre begränsningar för den förväntade uthoppstiden. En martingalmetod och en metod för normalfördelade stokastiska variabler ger undre begränsningar. Metoderna har alla både förtjänster och nackdelar. Genom att kombinera de olika metoderna får man de bästa resultaten. Vi får fram gränsvärdet för det asymptotiska beteendet hos en uthoppstid för den multivariata autoregressiva processen, samt motsvarande gränsvärde för den univariata autoregressiva processen av ordning n.

Combined selection in early generation testing of self-pollinated plants

Seven selection indexes based on the phenotypic value of the individual and the mean performance of its family were assessed for their application in breeding of self-pollinated plants. There is no clear superiority from one index to another although some show one or more negative aspects, such as favoring the selection of a top performing plant from an inferior family in detriment of an excellent plant from a superior family

The interaction of meal-related, rhythmic and homeostatic mechanisms and the generation of thirst and drinking

One of the primary goals of the study of thirst is to understand why drinking occurs under ad libitum or natural conditions. An appreciation of the experimental strategies applied by physiologists studying thirst from different perspectives can facilitate progress toward understanding the natural history of drinking behavior. Drinking research carried out using three separate perspectives - homeostatic, circadian rhythms, and food-associated - generates types of information about the mechanisms underlying drinking behavior. By combining research strategies and methods derived from each of these approaches, it has been possible to gain new information that increases our appreciation of the interactions between homeostatic mechanisms and circadian rhythms in the modulation of water intake and how these might be related to drinking associated with food intake under near natural conditions

The rate of force generation by the myocardium is not influenced by afterload

The influence of afterload on the rate of force generation by the myocardium was investigated using two types of preparations: the in situ dog heart (dP/dt) and isolated papillary muscle of rats (dT/dt). Thirteen anesthetized, mechanically ventilated and thoracotomized dogs were submitted to pharmacological autonomic blockade (3.0 mg/kg oxprenolol plus 0.5 mg/kg atropine). A reservoir connected to the left atrium permitted the control of left ventricular end-diastolic pressure (LVEDP). A mechanical constriction of the descending thoracic aorta allowed to increase the systolic pressure in two steps of 20 mmHg (conditions H1 and H2) above control values (condition C). After arterial pressure elevations (systolic pressure C: 119 ± 8.1; H1: 142 ± 7.9; H2 166 ± 7.7 mmHg; P<0.01), there were no significant differences in heart rate (C: 125 ± 13.9; H1: 125 ± 13.5; H2: 123 ± 14.1 bpm; P>0.05) or LVEDP (C: 6.2 ± 2.48; H1: 6.3 ± 2.43; H2: 6.1 ± 2.51 mmHg; P>0.05). The values of dP/dt did not change after each elevation of arterial pressure (C: 3,068 ± 1,057; H1: 3,112 ± 996; H2: 3,086 ± 980 mmHg/s; P>0.05). In isolated rat papillary muscle, an afterload corresponding to 50% and 75% of the maximal developed tension did not alter the values of the maximum rate of tension development (100%: 78 ± 13; 75%: 80 ± 13; 50%: 79 ± 11 g mm-2 s-1, P>0.05). The results show that the rise in afterload per se does not cause changes in dP/dt or dT/dt

Precipitated immune complexes of IgM induce the generation of reactive oxygen species by rabbit polymorphonuclear leucocytes

We report that immune complexes of IgM (ICIgM) antibodies and ovalbumin in the form of a precipitate from the equivalence zone induce the generation of reactive oxygen species by rabbit blood polymorphonuclear leucocytes (PMN), as measured by the chemiluminescence (CL) production in the presence of luminol. The kinetics of CL generation induced by ICIgM is quite different from that induced by precipitated immune complexes of IgG (ICIgG): the maximum rate of CL production for ICIgM occurs around 14 min, whereas for ICIgG it occurs about 5 min after incubation with the cells. Also the triggering of the process requires a higher concentration of ICIgM than of ICIgG. Evidence is presented that these effects are not mediated by interaction of the antigen (ovalbumin) with the cell, since immune precipitates of ovalbumin and the F(ab')2 fragment had no effect. Our observations that precipitated ICIgM can also be an effective stimulus for CL generation and thus for O2- production reveal a new functional capability of PMN. These results may have implications for the understanding of the participation of ICIgM (as well as of ICIgG) in inflammatory reactions mediated by PMN in immune complex diseases, and in the mechanisms of defense against microbes and other non-self agents.

Rapid eye movement sleep deprivation induces an increase in acetylcholinesterase activity in discrete rat brain regions

Some upper brainstem cholinergic neurons (pedunculopontine and laterodorsal tegmental nuclei) are involved in the generation of rapid eye movement (REM) sleep and project rostrally to the thalamus and caudally to the medulla oblongata. A previous report showed that 96 h of REM sleep deprivation in rats induced an increase in the activity of brainstem acetylcholinesterase (Achase), the enzyme which inactivates acetylcholine (Ach) in the synaptic cleft. There was no change in the enzyme's activity in the whole brain and cerebrum. The components of the cholinergic synaptic endings (for example, Achase) are not uniformly distributed throughout the discrete regions of the brain. In order to detect possible regional changes we measured Achase activity in several discrete rat brain regions (medulla oblongata, pons, thalamus, striatum, hippocampus and cerebral cortex) after 96 h of REM sleep deprivation. Naive adult male Wistar rats were deprived of REM sleep using the flower-pot technique, while control rats were left in their home cages. Total, membrane-bound and soluble Achase activities (nmol of thiocholine formed min-1 mg protein-1) were assayed photometrically. The results (mean ± SD) obtained showed a statistically significant (Student t-test) increase in total Achase activity in the pons (control: 147.8 ± 12.8, REM sleep-deprived: 169.3 ± 17.4, N = 6 for both groups, P<0.025) and thalamus (control: 167.4 ± 29.0, REM sleep-deprived: 191.9 ± 15.4, N = 6 for both groups, P<0.05). Increases in membrane-bound Achase activity in the pons (control: 171.0 ± 14.7, REM sleep-deprived: 189.5 ± 19.5, N = 6 for both groups, P<0.05) and soluble enzyme activity in the medulla oblongata (control: 147.6 ± 16.3, REM sleep-deprived: 163.8 ± 8.3, N = 6 for both groups, P<0.05) were also observed. There were no statistically significant differences in the enzyme's activity in the other brain regions assayed. The present findings show that the increase in Achase activity induced by REM sleep deprivation was specific to the pons, a brain region where cholinergic neurons involved in REM generation are located, and also to brain regions which receive cholinergic input from the pons (the thalamus and medulla oblongata). During REM sleep extracellular levels of Ach are higher in the pons, medulla oblongata and thalamus. The increase in Achase activity in these brain areas after REM sleep deprivation suggests a higher rate of Ach turnover.

Value of Information Logistics Integration in Digital Business Ecosystem

Digital business ecosystems (DBE) are becoming an increasingly popular concept for modelling and building distributed systems in heterogeneous, decentralized and open environments. Information- and communication technology (ICT) enabled business solutions have created an opportunity for automated business relations and transactions. The deployment of ICT in business-to-business (B2B) integration seeks to improve competitiveness by establishing real-time information and offering better information visibility to business ecosystem actors. The products, components and raw material flows in supply chains are traditionally studied in logistics research. In this study, we expand the research to cover the processes parallel to the service and information flows as information logistics integration. In this thesis, we show how better integration and automation of information flows enhance the speed of processes and, thus, provide cost savings and other benefits for organizations. Investments in DBE are intended to add value through business automation and are key decisions in building up information logistics integration. Business solutions that build on automation are important sources of value in networks that promote and support business relations and transactions. Value is created through improved productivity and effectiveness when new, more efficient collaboration methods are discovered and integrated into DBE. Organizations, business networks and collaborations, even with competitors, form DBE in which information logistics integration has a significant role as a value driver. However, traditional economic and computing theories do not focus on digital business ecosystems as a separate form of organization, and they do not provide conceptual frameworks that can be used to explore digital business ecosystems as value drivers—combined internal management and external coordination mechanisms for information logistics integration are not the current practice of a company’s strategic process. In this thesis, we have developed and tested a framework to explore the digital business ecosystems developed and a coordination model for digital business ecosystem integration; moreover, we have analysed the value of information logistics integration. The research is based on a case study and on mixed methods, in which we use the Delphi method and Internetbased tools for idea generation and development. We conducted many interviews with key experts, which we recoded, transcribed and coded to find success factors. Qualitative analyses were based on a Monte Carlo simulation, which sought cost savings, and Real Option Valuation, which sought an optimal investment program for the ecosystem level. This study provides valuable knowledge regarding information logistics integration by utilizing a suitable business process information model for collaboration. An information model is based on the business process scenarios and on detailed transactions for the mapping and automation of product, service and information flows. The research results illustrate the current cap of understanding information logistics integration in a digital business ecosystem. Based on success factors, we were able to illustrate how specific coordination mechanisms related to network management and orchestration could be designed. We also pointed out the potential of information logistics integration in value creation. With the help of global standardization experts, we utilized the design of the core information model for B2B integration. We built this quantitative analysis by using the Monte Carlo-based simulation model and the Real Option Value model. This research covers relevant new research disciplines, such as information logistics integration and digital business ecosystems, in which the current literature needs to be improved. This research was executed by high-level experts and managers responsible for global business network B2B integration. However, the research was dominated by one industry domain, and therefore a more comprehensive exploration should be undertaken to cover a larger population of business sectors. Based on this research, the new quantitative survey could provide new possibilities to examine information logistics integration in digital business ecosystems. The value activities indicate that further studies should continue, especially with regard to the collaboration issues on integration, focusing on a user-centric approach. We should better understand how real-time information supports customer value creation by imbedding the information into the lifetime value of products and services. The aim of this research was to build competitive advantage through B2B integration to support a real-time economy. For practitioners, this research created several tools and concepts to improve value activities, information logistics integration design and management and orchestration models. Based on the results, the companies were able to better understand the formulation of the digital business ecosystem and the importance of joint efforts in collaboration. However, the challenge of incorporating this new knowledge into strategic processes in a multi-stakeholder environment remains. This challenge has been noted, and new projects have been established in pursuit of a real-time economy.

Establishment of new murine embryonic stem cell lines for the generation of mouse models of human genetic diseases

Embryonic stem cells are totipotent cells derived from the inner cell mass of blastocysts. Recently, the development of appropriate culture conditions for the differentiation of these cells into specific cell types has permitted their use as potential therapeutic agents for several diseases. In addition, manipulation of their genome in vitro allows the creation of animal models of human genetic diseases and for the study of gene function in vivo. We report the establishment of new lines of murine embryonic stem cells from preimplantation stage embryos of 129/Sv mice. Most of these cells had a normal karyotype and an XY sex chromosome composition. The pluripotent properties of the cell lines obtained were analyzed on the basis of their alkaline phosphatase activity and their capacity to form complex embryoid bodies with rhythmically contracting cardiomyocytes. Two lines, USP-1 and USP-3, with the best in vitro characteristics of pluripotency were used in chimera-generating experiments. The capacity to contribute to the germ line was demonstrated by the USP-1 cell line. This cell line is currently being used to generate mouse models of human diseases.

On Distributed Storage Codes

Distributed storage systems are studied. The interest in such system has become relatively wide due to the increasing amount of information needed to be stored in data centers or different kinds of cloud systems. There are many kinds of solutions for storing the information into distributed devices regarding the needs of the system designer. This thesis studies the questions of designing such storage systems and also fundamental limits of such systems. Namely, the subjects of interest of this thesis include heterogeneous distributed storage systems, distributed storage systems with the exact repair property, and locally repairable codes. For distributed storage systems with either functional or exact repair, capacity results are proved. In the case of locally repairable codes, the minimum distance is studied. Constructions for exact-repairing codes between minimum bandwidth regeneration (MBR) and minimum storage regeneration (MSR) points are given. These codes exceed the time-sharing line of the extremal points in many cases. Other properties of exact-regenerating codes are also studied. For the heterogeneous setup, the main result is that the capacity of such systems is always smaller than or equal to the capacity of a homogeneous system with symmetric repair with average node size and average repair bandwidth. A randomized construction for a locally repairable code with good minimum distance is given. It is shown that a random linear code of certain natural type has a good minimum distance with high probability. Other properties of locally repairable codes are also studied.

A third generation regimen VACOP-B with or without adjuvant radiotherapy for aggressive localized non-Hodgkin's lymphoma: report from the Italian Non-Hodgkin's Lymphoma Co-operative Study Group

The objective of this multicenter prospective study was to determine the clinical efficacy and toxicity of a polychemotherapeutic third generation regimen, VACOP-B, with or without radiotherapy as front-line therapy in aggressive localized non-Hodgkin's lymphoma. Ninety-three adult patients (47 males and 46 females, median age 45 years) with aggressive localized non-Hodgkin's lymphoma, 43 in stage I and 50 in stage II (non-bulky), were included in the study. Stage I patients received VACOP-B for 6 weeks plus involved field radiotherapy and stage II patients received 12 weeks VACOP-B plus involved field radiotherapy on residual masses. Eighty-six (92.5%) achieved complete remission and 4 (4.3%) partial remission. Three patients (3.2%) were primarily resistant. Ten-year probability of survival, progression-free survival and disease-free survival were 87.3, 79.9 and 83.9%, respectively. Eighty-four patients are surviving at a median observation time of 57 months (range: 6-126). Statistical analysis showed no difference between stages I and II in terms of response, ten-year probability of survival, progression-free survival or disease-free survival. Side effects and toxicity were negligible and were similar in the two patient groups. The results of this prospective study suggest that 6 weeks of VACOP-B treatment plus radiotherapy may be the therapy of choice in stage I aggressive non-Hodgkin's lymphoma. Twelve weeks of VACOP-B treatment with or without radiotherapy was shown to be effective and feasible for stage II. These observations need to be confirmed by a phase III study comparing first and third generation protocols in stage I-II aggressive non-Hodgkin's lymphoma.

A simple model for circadian timing by mammals

Circadian timing is structured in such a way as to receive information from the external and internal environments, and its function is the timing organization of the physiological and behavioral processes in a circadian pattern. In mammals, the circadian timing system consists of a group of structures, which includes the suprachiasmatic nucleus (SCN), the intergeniculate leaflet and the pineal gland. Neuron groups working as a biological pacemaker are found in the SCN, forming a biological master clock. We present here a simple model for the circadian timing system of mammals, which is able to reproduce two fundamental characteristics of biological rhythms: the endogenous generation of pulses and synchronization with the light-dark cycle. In this model, the biological pacemaker of the SCN was modeled as a set of 1000 homogeneously distributed coupled oscillators with long-range coupling forming a spherical lattice. The characteristics of the oscillator set were defined taking into account the Kuramoto's oscillator dynamics, but we used a new method for estimating the equilibrium order parameter. Simultaneous activities of the excitatory and inhibitory synapses on the elements of the circadian timing circuit at each instant were modeled by specific equations for synaptic events. All simulation programs were written in Fortran 77, compiled and run on PC DOS computers. Our model exhibited responses in agreement with physiological patterns. The values of output frequency of the oscillator system (maximal value of 3.9 Hz) were of the order of magnitude of the firing frequencies recorded in suprachiasmatic neurons of rodents in vivo and in vitro (from 1.8 to 5.4 Hz).

Pharmacogenetic polymorphisms in Brazilian-born, first-generation Japanese descendants

Brazil hosts the largest Japanese community outside Japan, estimated at 1.5 million individuals, one third of whom are first-generation, Brazilian-born with native Japanese parents. This large community provides a unique opportunity for comparative studies of the distribution of pharmacogenetic polymorphisms in native Japanese versus their Brazilian-born descendants. Functional polymorphisms in genes that modulate drug disposition (CYP2C9, CYP2C19 and GSTM3) or response (VKORC1) and that differ significantly in frequency in native Japanese versus Brazilians with no Japanese ancestry were selected for the present study. Healthy subjects (200 native Japanese and 126 first-generation Japanese descendants) living in agricultural colonies were enrolled. Individual DNA was genotyped using RFLP (GSTM3*A/B) or TaqMan Detection System assays (CYP2C9*2 and *3; CYP2C19*2 and *3; VKORC1 3673G>A, 5808T>G, 6853G>C, and 9041G>A). No difference was detected in the frequency of these pharmacogenetic polymorphisms between native Japanese and first-generation Japanese descendants. In contrast, significant differences in the frequency of each polymorphism were observed between native or first-generation Japanese and Brazilians with no Japanese ancestry. The VKORC1 3673G>A, 6853G>C and 9041G>A single nucleotide polymorphisms were in linkage disequilibrium in both native and first-generation Japanese living in Brazil. The striking similarity in the frequency of clinically relevant pharmacogenetic polymorphisms between Brazilian-born Japanese descendants and native Japanese suggests that the former may be recruited for clinical trials designed to generate bridging data for the Japanese population in the context of the International Conference on Harmonization.

Alternative pathways for angiotensin II generation in the cardiovascular system

The classical renin-angiotensin system (RAS) consists of enzymes and peptides that regulate blood pressure and electrolyte and fluid homeostasis. Angiotensin II (Ang II) is one of the most important and extensively studied components of the RAS. The beneficial effects of angiotensin converting enzyme (ACE) inhibitors in the treatment of hypertension and heart failure, among other diseases, are well known. However, it has been reported that patients chronically treated with effective doses of these inhibitors do not show suppression of Ang II formation, suggesting the involvement of pathways alternative to ACE in the generation of Ang II. Moreover, the finding that the concentration of Ang II is preserved in the kidney, heart and lungs of mice with an ACE deletion indicates the important role of alternative pathways under basal conditions to maintain the levels of Ang II. Our group has characterized the serine protease elastase-2 as an alternative pathway for Ang II generation from Ang I in rats. A role for elastase-2 in the cardiovascular system was suggested by studies performed in heart and conductance and resistance vessels of normotensive and spontaneously hypertensive rats. This mini-review will highlight the pharmacological aspects of the RAS, emphasizing the role of elastase-2, an alternative pathway for Ang II generation.

Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines

Pancreatic cancer is the fourth leading cause of cancer death. Gemcitabine is widely used as a chemotherapeutic agent for the treatment of pancreatic cancer, but the prognosis is still poor. Berberine, an isoquinoline alkaloid extracted from a variety of natural herbs, possesses a variety of pharmacological properties including anticancer effects. In this study, we investigated the anticancer effects of berberine and compared its use with that of gemcitabine in the pancreatic cancer cell lines PANC-1 and MIA-PaCa2. Berberine inhibited cell growth in a dose-dependent manner by inducing cell cycle arrest and apoptosis. After berberine treatment, the G1 phase of PANC-1 cells increased by 10% compared to control cells, and the G1 phase of MIA-PaCa2 cells was increased by 2%. Whereas gemcitabine exerts antiproliferation effects through S-phase arrest, our results showed that berberine inhibited proliferation by inducing G1-phase arrest. Berberine-induced apoptosis of PANC-1 and MIA-PaCa2 cells increased by 7 and 2% compared to control cells, respectively. Notably, berberine had a greater apoptotic effect in PANC-1 cells than gemcitabine. Upon treatment of PANC-1 and MIA-PaCa2 with berberine at a half-maximal inhibitory concentration (IC50), apoptosis was induced by a mechanism that involved the production of reactive oxygen species (ROS) rather than caspase 3/7 activation. Our findings showed that berberine had anti-cancer effects and may be an effective drug for pancreatic cancer chemotherapy.

Load balancing in P2P smartphone based distributed IoT systems

With the new age of Internet of Things (IoT), object of everyday such as mobile smart devices start to be equipped with cheap sensors and low energy wireless communication capability. Nowadays mobile smart devices (phones, tablets) have become an ubiquitous device with everyone having access to at least one device. There is an opportunity to build innovative applications and services by exploiting these devices’ untapped rechargeable energy, sensing and processing capabilities. In this thesis, we propose, develop, implement and evaluate LoadIoT a peer-to-peer load balancing scheme that can distribute tasks among plethora of mobile smart devices in the IoT world. We develop and demonstrate an android-based proof of concept load-balancing application. We also present a model of the system which is used to validate the efficiency of the load balancing approach under varying application scenarios. Load balancing concepts can be apply to IoT scenario linked to smart devices. It is able to reduce the traffic send to the Cloud and the energy consumption of the devices. The data acquired from the experimental outcomes enable us to determine the feasibility and cost-effectiveness of a load balanced P2P smart phone-based applications.