Perfectly Balanced Boolean Functions and Golić Conjecture

Golić conjecture states that the necessary condition for a function to be perfectly balanced for any choice of a tapping sequence is linearity of a function in the first or in the last essential variable. In the current paper we prove Golić conjecture

Toll-like Receptor 9 (TLR9) activation and the innate immune response to microbial and human DNA

The human Toll-like Receptor 9 (TLR9) is an endosomal Pattern Recognition Receptor (PRR) that recognizes DNA sequences containing the unmethylated Cytosine-Guanine (CpG) dimers, which are present in greater abundance in most bacterial genomes compared to those of vertebrates. Specific CpG-containing sequences are strongly stimulatory of human TLR9, as shown in published studies using synthetic oligonucleotides (ODN) and DNA from bacterial species of varying genomic CpG concentration. Human TLR9 activation was experimentally examined in this thesis using DNA extracted from different bacterial sources, human DNA from Caco-2 cells, known immunostimulatory ODN, and short ODN. In vitro assays using fragment length-standardized microbial genomic DNA on HEK-Dual TLR9 Cells and human peripheral blood mononuclear cells (PBMCs) revealed that TLR9 activation strongly correlated to CpG concentration of the input DNA, with an additional influence of CpG-containing 5-mer TCGTT concentration. When DNA of varying origins and fragment lengths were used together, however, complex dynamics of TLR9 activation, co-activation, and repression were observed, which were less predictable than expected from genomic CpG concentration alone. DNase I-treated microbial DNA fragments of less than 15 bp of length were non-activating on their own, but co-activated human TLR9 together with ODN-2006 in Ramos Blue (B) cells. Similarly, human DNA fragments at the length of 50-200 bp co-activated human TLR9 with both ODN-2006 and Escherichia coli DNA in HEK-dual TLR9 cells. In contrast, large human DNA fragments at over 10000 bp of length repressed TLR9 activation by ODN-2006 in Ramos Blue cells. Finally, a preliminary study was conducted in HT-29 cells on the effect of TLR9 activation on the invasion of Fusobacterium nucleatum, an opportunistic gut pathogen with a very low genomic CpG concentration at 0.296%, using ODN-2006 and human DNA as TLR9 activators. While increased presence of intracellular Fusobacterium nucleatum upon treatment with both ODN-2006 and human DNA was noted, more studies are needed to confirm TLR9 activation as a cause of greater bacterial invasion. The human colon is the location of the largest microbial population of the human body, which provides a rich source of non-human DNA in contact with human TLR9 present in intestinal epithelial cells, plasmacytoid dendritic cells (pDCs), and B lymphocytes. Additionally, the daily mass shedding and death of human intestinal epithelial cells provide large amounts of human DNA, which when combined with microbial DNA could result in co-activation and possible autoimmunity. The thesis thus provided an in vitro model of TLR9 activation by complex DNA of varying origins and fragment lengths likely to present in the human gut environment, and prepared a working basis for future studies of TLR9 activation by human fecal metagenomic DNA.Der menschliche Toll-like-Rezeptor 9 (TLR9) ist ein endosomaler Mustererkennungsrezeptor (PRR), der DNA-Sequenzen erkennt, die unmethylierte Cytosin-Guanin-Dimere (CpG) enthalten. Diese sind in den meisten bakteriellen Genomen in größerer Menge vorhanden als im Vergleich zu denen von Wirbeltieren. Spezifische CpG-haltige Sequenzen stimulieren den menschlichen TLR9 unterschiedlich stark, wie in veröffentlichten Studien mit synthetischen Oligonukleotiden (ODN) und DNA von Bakterienarten mit unterschiedlicher genomischer CpG-Konzentration zeigten. In der vorliegenden Arbeit wurde die Aktivierung des menschlichen TLR9 unter Verwendung von DNA aus verschiedenen bakteriellen Quellen, menschliche DNA aus Caco-2-Zellen, bekannte immunstimulierende ODN und kurze ODN experimentell untersucht. In in-vitro-Assays, in denen die TLR9 Aktivierung durch, mit Fragmentlängen-standardisierte mikrobielle genomische DNA in HEK-Dual TLR9-Zellen und humanen peripheren mononukleären Blutzellen (PBMCs) untersucht würde, zeigten dass die TLR9-Aktivierung stark mit der CpG-Konzentration Input-DNA korreliert und die CpG-haltige 5-mer TCGTT-Konzentration einen zusätzlichen Einfluss hat. Wurden jedoch DNAs unterschiedlicher Herkunft und Fragmentlängen zusammen verwendet, konnte eine komplexe Dynamik der TLR9-Aktivierung, Koaktivierung und Unterdrückung beobachtet werden, die weniger vorhersehbar war als von der genomischen CpG-Konzentration allein erwartet. Mikrobielle DNA-Fragmente mit einer Länge von weniger als 15 Basenpaaren (bp), welche mit DNase I behandelte wurden, besaßen alleine keine aktivierende Funktion. Im Zusammenspiel mit ODN-2006, konnte jedoch eine Aktivierung zusammen des menschlichen TLR9 in Ramos Blue (B)-Zellen beobachtet werden. In ähnlicher Weise ko-aktivierten menschliche DNA-Fragmente mit einer Länge von 50-200 bp den menschlichen TLR9, sowohl unter Zugabe von ODN-2006, als auch Escherichia coli DNA in HEK-dual TLR9-Zellen. Im Gegensatz dazu unterdrückten große menschliche DNA-Fragmente mit einer Länge von über 10000 bp die TLR9-Aktivierung durch ODN-2006 in Ramos Blue-Zellen. Schließlich wurde eine vorläufige Studie über die Auswirkungen der TLR9-Aktivierung in HT-29-Zellen auf die Invasion von Fusobacterium nucleatum, einem opportunistischen Darmpathogen mit einer sehr niedrigen genomischen CpG-Konzentration von 0,296%, durchgeführt. Als TLR9-Aktivatoren wurden dabei ODN-2006 und menschliche DNA verwendet. Während eine erhöhte Präsenz von intrazellulärem Fusobacterium nucleatum nach der Behandlung sowohl mit ODN-2006 als auch mit menschlicher DNA festgestellten wurde, sind weitere Studien erforderlich, um die TLR9-Aktivierung als Ursache für eine stärkere bakterielle Invasion zu bestätigen. Der menschliche Dickdarm beherbergt die größte mikrobielle Population des menschlichen Körpers. Diese stellt eine reichhaltige Quelle nicht-menschlicher DNA dar, die mit menschlichem TLR9 in intestinalen Epithelzellen, plasmazytoiden dendritischen Zellen (pDCs) und B-Lymphozyten in Kontakt kommt. Darüber hinaus liefern die täglichen Ausscheidungen und das Absterben menschlicher Darmepithelzellen große Mengen menschlicher DNA, die in Kombination mit mikrobieller DNA zu einer Koaktivierung und möglicher Autoimmunität führen könnten. Die Arbeit lieferte somit ein in-vitro-Modell der TLR9-Aktivierung durch komplexe DNA unterschiedlicher Herkunft und Fragmentlänge, wie sie in der menschlichen Darmumgebung vorkommen kann, und bereitete eine Arbeitsgrundlage für künftige Studien zur TLR9-Aktivierung durch menschliche fäkale metagenomische DNA

Gas Discharge Visualization (Electrophotonic Imaging, Kirlianography). Theoretical and Applied Aspects, 189 s.

The monograph highlights the results of priority clinical-physiological studies of the relationships between gas discharge visualization (electrophotonic imaging, kirlianography) parameters, on the one hand, and electroencephalograms, heart rate variability, immunograms, phagocytosis, the content of the main adaptation hormones (cortisol, aldosterone, testosterone, triiodothyronine, calcitonin) in the blood as well as acupuncture points - on the other hand. It is shown that the GDV/EPI method reliably reflects the state of the body's neuro-endocrine-immune complex as well as others parameters and has the right to take its place in the arsenal of physiological/biophysical methods. For biophysicists, physiologists, psychophysiologists, endocrinologists, immunologists, medical rehabilitation specialists. INTRODUCTION Advances in biophysics, biology, functional genomics, neuroscience, psychology, psychoneuroimmunology, and other fields suggest the existence of a subtle system of “biofield” interactions that organize biological processes from the subatomic, atomic, molecular, cellular, and organismic to the interpersonal and cosmic levels. Biofield interactions may bring about regulation of biochemical, cellular, and neurological processes through means related to electromagnetism, quantum fields, and perhaps other means of modulating biological activity and information flow. The biofield paradigm, in contrast to a reductionist, chemistry-centered viewpoint, emphasizes the informational content of biological processes; biofield interactions are thought to operate in part via low-energy or “subtle” processes such as weak, nonthermal electromagnetic fields (EMFs) or processes potentially related to consciousness and nonlocality. Biofield interactions may also operate through or be reflected in more well-understood informational processes found in EEG and ECG data. Recent advances have led to the development of a wide variety of therapeutic and diagnostic biofield devices, defined as physical instruments best understood from the viewpoint of a biofield paradigm [Muehsam D et al, 2015]. Biofield devices comprise physical instruments that may be most clearly understood from the viewpoint of a biofield paradigm, and a large and diverse number of devices have been developed to measure or manipulate biofield interactions. These include both diagnostic devices (to measure biofield properties) and therapeutic devices (to manipulate biofield interactions). The study of biofield devices is at a nascent stage of development, and much further research is needed to determine clinical efficacy and elucidate the underlying mechanisms of action for many of the devices mentioned here. The biofield devices operate through a variety of modalities rather than a single mechanism. Some biofield devices function through well-understood mechanisms and are already widely used in clinical settings: for example, electroencephalography (EEG)- and electrocardiography (ECG)-based heart rate variability (HRV). Other devices appear to operate through mechanisms that are novel or incompletely understood. However, all of these devices share a common property: rather than functioning primarily in a reductionist, chemistry-centered manner, biofield devices function via the informational content of biological processes and can interact via low-energy or “subtle” processes, including those potentially related to consciousness and nonlocality [Muehsam D et al, 2015]. Here Muehsam D et al [2015] provide a brief overview of the broad categories of biofield devices, with the goal being to stimulate further discussion and research. Authors describe those devices for which thay deemed that sufficient evidence exists to warrant mention. They chose to focus upon devices for which peer-reviewed scientific reports suggesting efficacy are available rather than conference proceedings or manufacturers' white papers. However, in the few cases that specific devices with sufficient promise and relevance lacked a peer-reviewed basis, authors have presented whatever evidence was available. Here, devices are organized according to mode of operation and these modalities include electromagnetic field (EMF)-light, EMF-heat, EMF-nonthermal, electrical current, vibration and sound, physical and mechanical, intentionality and nonlocality, gas and plasma, and other (mode of operation not well understood). Muehsam D et al [2015] deemed that gas discharge visualization (GDV) is an important example of the use of plasma in biofield science. Back in 1880 Nikola Tesla demonstrated that when placing the man in the high-frequency field around the body there is a bright glow [cit. by Korotkov KG, 2001]. In 1892 Nardkevych-Yodko YO recorded glow human hands on photographic plate [cit. by Ciesielska I, 2009]. However, a well-known method of "high-frequency photography" was due to spouses Kirlian SD&VH who in 1939 independently discovered this phenomenon [Kirlian SD & Kirlian VKh, 1961], later called "Kirlian’s effect". This technique has been called corona discharge photography [Boyers DG & Tiller WA, 1973], electrophotography [Earle L, 1975], electrography [Konikiewicz LW, 1979], GDV [Bankovskii NG et al, 1986]. In 1996 Korotkov KG created a new scientific approach, based on the digital videotechnics, modern electronics and computer processing quantitative data, called as method gas discharge visualization (GDV bioelectrography). Parallel uses the terms Kirlianography and Electrophotonic imaging (EPI) [Korotkov KG, 2001; 2007; 2014; Korotkov KG et al, 2002; Wisneski LA & Anderson L, 2009; Jakovleva E & Korotkov K, 2013]. Method of GDV, essence of which consists in registration of photoelectronic emission of skin, induced by high-frequency electromagnetic impulses, allows to estimate integrated psycho-somatic state of organism. The first base parameter of GDV is Area of Gas Discharge Image (GDI) in Right, Frontal and Left projections registered both with and without polyethylene filter. The second base parameter is a coefficient of form/shape (ratio of square of length of external contour of GDI toward his area), which characterizes the measure of serration/fractality of external contour. The third base parameter of GDI is Entropy, id est measure of chaos. It is considered that GDI, taken off without filter, characterizes the functional changes of organism, and with a filter characterizes organic changes. Program estimates also Energy and Asymmetry of virtual Chakras [Korotkov KG, 2001; 2007; 2014]. Nearly 1000 papers have been published (mostly in Russian) on GDV research and a few hundred more in the West. These intriguing data suggest that informatics based upon biofield measurement devices such as the GDV may be useful for gaining deeper understanding of disease states and guiding practitioners and their patients towards states of greater wellness [Muehsam D et al, 2015]. Without regard to the wideuse enough of method in medicine, psychology, valeology and others like that, he yields to the just criticizing for an insufficient physiology ground. There fore we put before itself sweep to analyse relationships between the parameters of GDV - from one side, and by the row of neurodynamics, endocrine, immune. psychophysiological, and other parameters - on the other hand

Psychoneural reduction: a perspective from neural circuits

Abstract: Psychoneural reduction has been debated extensively in the philosophy of neuroscience. In this article I will evaluate metascientific approaches that claim direct molecular and cellular explanations of cognitive functions. I will initially consider the issues involved in linking cellular properties to behaviour from the general perspective of neural circuits. These circuits that integrate the molecular and cellular components underlying cognition and behaviour, making consideration of circuit properties relevant to reductionist debates. I will then apply this general perspective to specific systems where psychoneural reduction has been claimed, namely hippocampal long-term potentiation and the Aplysia gill-withdrawal reflex

ARTIFICIAL IMMUNE SYSTEMS FOR INFORMATION FILTERING: FOCUSING ON PROFILE ADAPTATION

The human immune system has characteristics such as self-organisation, robustness and adaptivity that may be useful in the development of adaptive systems. One suitable application area for adaptive systems is Information Filtering (IF). Within the context of IF, learning and adapting user profiles is an important research area. In an individual profile, an IF system has to rely on the ability of the user profile to maintain a satisfactory level of filtering accuracy for as long as it is being used. This thesis explores a possible way to enable Artificial Immune Systems (AIS) to filter information in the context of profile adaptation. Previous work has investigated this issue from the perspective of self-organisation based on Autopoetic Theory. In contrast, this current work approaches the problem from the perspective of diversity inspired by the concept of dynamic clonal selection and gene library to maintain sufficient diversity. An immune inspired IF for profile adaptation is proposed and developed. This algorithm is demonstrated to work in detecting relevant documents by using a single profile to recognize a user’s interests and to adapt to changes in them. We employed a virtual user tested on a web document corpus to test the profile on learning of an emerging new topic of interest and forgetting uninteresting topics. The results clearly indicate the profile’s ability to adapt to frequent variations and radical changes in user interest. This work has focused on textual information, but it may have the potential to be applied in other media such as audio and images in which adaptivity to dynamic environments is crucial. These are all interesting future directions in which this work might develop

Investigation into the migration of Leishmania within Phlebotomine sand flies

Protozoan parasites of the genus Leishmania are the causative agents of a wide spectrum of diseases from self-healing cutaneous leishmaniasis to visceral leishmaniasis. The parasites undergo a complex life cycle including motile and nonmotile cell types within the insect vector and vertebrate host. Within the insect vector, promastigotes generally migrate anteriorly along the gut as they undergo morphological changes from procyclic to nectomonad and later to metacyclic form of promastigotes. In order for the insect vector to transmit infective stage Leishmania promastigotes to the mammalian host via a blood feed, metacyclic promastigotes need to be located within the foregut. The study of the elicitors of migration within the sand fly alimentary canal have to date been fragmentary with no exploration of the different promastigote forms and the effects of the vast array of potential chemoeffectors present. Two Leishmania species were selected based on their migration properties in the sand fly gut. This study focussed on understanding the chemotaxis of different morphotypes of posterior migrating reptilian- pathogenic Leishmania tarentolae compared to the anterior migrating human pathogenic Leishmania mexicana within the biochemical gradients of the sand fly alimentary canal. This study explored the movement of both L. mexicana and L. tarentolae promastigotes towards a gradient of urea that may be found emitting from Malpighian tubules in the hindgut, the novel morphologies of L. tarentolae, the migration of procyclics, neptomonads, leptomonads and metacyclics, and the development of a novel microfluidic device for the study of chemotaxis in Leishmania. The results from the chemotaxic assays suggested that the migration of promastigotes occurred through the attraction towards cues such as the urea gradient from the Malpighian tubules and hindgut, and the sugars gradient from the diverticulum. These assays showed that L. tarentolae had a significantly higher attraction to urea and L.mexicana to sugars; confirming the species-specific differences between suprapylarian and hypopylarian parasites. Using different populations of L. mexicana and L.tarentolae promastigotes, a significant difference in migration between population based on age was observed. The results also suggested that a population rich in leptomonads and nectomonads had a higher migration and therefore a higher attraction towards the chemical cues. The results shed light on parasite migration that is dependent on the developmental stage of promastigotes as well as the speciesspecific cues. The role that the cues play in determining which Leishmania species can be transmitted via the bite of a sandfly are discussed