Palaeolithic Populations and Waves of Advance

The wave-of-advance model has been previously applied to Neolithic human range expansions, yielding good agreement to the speeds inferred from archaeological data. Here, we apply it for the first time to Palaeolithic human expansions by using reproduction and mobility parameters appropriate to hunter-gatherers (instead of the corresponding values for preindustrial farmers). The order of magnitude of the predicted speed is in agreement with that implied by the AMS radiocarbon dating of the lateglacial human recolonization of northern Europe (14.2–12.5 kyr BP). We argue that this makes it implausible for climate change to have limited the speed of the recolonization front. It is pointed out that a similar value for the speed can be tentatively inferred from the archaeological data on the expansion of modern humans into the Levant and Europe (42–36 kyr BP)

Dispersion of Hybrid Electromagnetic-Spin Waves in the Slotline

The presented thesis is devoted to investigation of wave processes in hybrid ferrite / ferroelectric structures. Spin wave devices based on ferrite films have such disadvantages, as huge size of the magnetic systems, low tuning velocity, considerable power inputs for parameters control that limits possible device applications. The considered layered structures allow to overcome the disadvantages mentioned and to promote the development of novel class of tunable microwave devices. The proposed theoretical analysis is intended to construct a model of hybrid electromagnetic-spin waves. Based on the theoretical analysis the experimental investigations were carried out. The experimental resonance characteristics of ferrite / ferroelectric resonator were obtained and their tunability by means of magnetic and electric field was demonstrated.

Methods for construction and analysis of computational models in systems biology : applications to the modelling of the heat shock response and the self-assembly of intermediate filaments

Systems biology is a new, emerging and rapidly developing, multidisciplinary research field that aims to study biochemical and biological systems from a holistic perspective, with the goal of providing a comprehensive, system- level understanding of cellular behaviour. In this way, it addresses one of the greatest challenges faced by contemporary biology, which is to compre- hend the function of complex biological systems. Systems biology combines various methods that originate from scientific disciplines such as molecu- lar biology, chemistry, engineering sciences, mathematics, computer science and systems theory. Systems biology, unlike “traditional” biology, focuses on high-level concepts such as: network, component, robustness, efficiency, control, regulation, hierarchical design, synchronization, concurrency, and many others. The very terminology of systems biology is “foreign” to “tra- ditional” biology, marks its drastic shift in the research paradigm and it indicates close linkage of systems biology to computer science. One of the basic tools utilized in systems biology is the mathematical modelling of life processes tightly linked to experimental practice. The stud- ies contained in this thesis revolve around a number of challenges commonly encountered in the computational modelling in systems biology. The re- search comprises of the development and application of a broad range of methods originating in the fields of computer science and mathematics for construction and analysis of computational models in systems biology. In particular, the performed research is setup in the context of two biolog- ical phenomena chosen as modelling case studies: 1) the eukaryotic heat shock response and 2) the in vitro self-assembly of intermediate filaments, one of the main constituents of the cytoskeleton. The range of presented approaches spans from heuristic, through numerical and statistical to ana- lytical methods applied in the effort to formally describe and analyse the two biological processes. We notice however, that although applied to cer- tain case studies, the presented methods are not limited to them and can be utilized in the analysis of other biological mechanisms as well as com- plex systems in general. The full range of developed and applied modelling techniques as well as model analysis methodologies constitutes a rich mod- elling framework. Moreover, the presentation of the developed methods, their application to the two case studies and the discussions concerning their potentials and limitations point to the difficulties and challenges one encounters in computational modelling of biological systems. The problems of model identifiability, model comparison, model refinement, model inte- gration and extension, choice of the proper modelling framework and level of abstraction, or the choice of the proper scope of the model run through this thesis.

Role and regulatory mechanisms of heat shock factor 2

Protein homeostasis is essential for cells to prosper and survive. Various forms of stress, such as elevated temperatures, oxidative stress, heavy metals or bacterial infections cause protein damage, which might lead to improper folding and formation of toxic protein aggregates. Protein aggregation is associated with serious pathological conditions such as Alzheimer’s and Huntington’s disease. The heat shock response is a defense mechanism that protects the cell against protein-damaging stress. Its ancient origin and high conservation among eukaryotes suggest that the response is crucial for survival. The main regulator of the heat shock response is the transcription factor heat shock factor 1 (HSF1), which induces transcription of genes encoding protective molecular chaperones. In vertebrates, a family of four HSFs exists (HSF1-4), with versatile functions not only in coping with acute stress, but also in development, longevity and cancer. Thus, knowledge of the HSFs will aid in our understanding on how cells survive suboptimal circumstances, but will also provide insights into normal physiological processes as well as diseaseassociated conditions. In this study, the function and regulation of HSF2 have been investigated. Earlier gene inactivation experiments in mice have revealed roles for HSF2 in development, particularly in corticogenesis and spermatogenesis. Here, we demonstrate that HSF2 holds a role also in the heat shock response and influences stress-induced expression of heat shock proteins. Intriguingly, DNA-binding activity of HSF2 upon stress was dependent on the presence of intact HSF1, suggesting functional interplay between HSF1 and HSF2. The underlying mechanism for this phenomenon could be configuration of heterotrimers between the two factors, a possibility that was experimentally verified. By changing the levels of HSF2, the expression of HSF1-HSF2 heterotrimer target genes was altered, implementing HSF2 as a modulator of HSF-mediated transcription. The results further indicate that HSF2 activity is dependent on its concentration, which led us to ask the question of how accurate HSF2 levels are achieved. Using mouse spermatogenesis as a model system, HSF2 was found to be under direct control of miR-18, a miRNA belonging to the miR-17~92 cluster/Oncomir-1 and whose physiological function had remained unclear. Investigations on spermatogenesis are severely hampered by the lack of cell systems that would mimic the complex differentiation processes that constitute male germ cell development. Therefore, to verify that HSF2 is regulated by miR-18 in spermatogenesis, a novel method named T-GIST (Transfection of Germ cells in Intact Seminiferous Tubules) was developed. Employing this method, the functional consequences of miR-18-mediated regulation in vivo were demonstrated; inhibition of miR- 18 led to increased expression of HSF2 and altered the expression of HSF2 target genes Ssty2 and Speer4a. Consequently, the results link miR-18 to HSF2-mediated processes such as germ cell maturation and quality control and provide miR-18 with a physiological role in gene expression during spermatogenesis.Taken together, this study presents compelling evidence that HSF2 is a transcriptional regulator in the heat shock response and establishes the concept of physical interplay between HSF2 and HSF1 and functional consequences thereof. This is also the first study describing miRNA-mediated regulation of an HSF.

Effect of wave frequency on the nonlinear interaction between Görtler vortices and three-dimensional Tollmien-Schlichting waves

The nonlinear interaction between Görtler vortices (GV) and three-dimensional Tollmien-Schlichting (TS) waves nonlinear interaction is studied with a spatial, nonparallel model based on the Parabolized Stability Equations (PSE). In this investigation the effect of TS wave frequency on the nonlinear interaction is studied. As verified in previous investigations using the same numerical model, the relative amplitudes and growth rates are the dominant parameters in GV/TS wave interaction. In this sense, the wave frequency influence is important in defining the streamwise distance traveled by the disturbances in the unstable region of the stability diagram and in defining the amplification rates that they go through.

A survey of the generation of ocean waves in a test basin

At present stage the analytical design of wave tolerance for floating structures and vessels is still imperfect due to the mutually complex and nonlinear phenomena between structures and waves. Wave tolerance design is usually carried out through iterative evaluations of results from model tests in a wave basin, and this is done in order to reach a final structural design. The wave generation has then become an important technology in the field of the coastal and ocean engineering. This paper summarizes the facilities of a test basin and a wave maker in Japan and also surveys the methodology of the generation of ocean waves in a test basin.

Acceleration of Solar Energetic Particles in coronal shocks through self-generated turbulence

The acceleration of solar energetic particles (SEPs) by flares and coronal mass ejections (CMEs) has been a major topic of research for the solar-terrestrial physics and geophysics communities for decades. This thesis discusses theories describing first-order Fermi acceleration of SEPs through repeated crossings at a CME-driven shock. We propose that particle trapping occurs through self-generated Alfvén waves, leading to a turbulent trapping region in front of the shock. Decelerating coronal shocks are shown to be capable of efficient SEP acceleration, provided seed particle injection is sufficient. Quasi-parallel shocks are found to inject thermal particles with good efficiency. The roles of minimum injection velocities, cross-field diffusion, downstream scattering efficiency and cross-shock potential are investigated in detail, with downstream isotropisation timescales having a major effect on injection efficiency. Accelerated spectra of heavier elements up to iron are found to exhibit significantly harder spectra than protons. Accelerated spectra cut-off energies are found to scale proportional to (Q/A)^1.5, which is explained through analysis of the spectral shape of amplified Alfvénic turbulence. Acceleration times to different threshold energies are found to be non-linear, indicating that self-consistent time-dependent simulations are required in order to expose the full extent of acceleration dynamics. The well-established quasilinear theory (QLT) of particle scattering is investigated by comparing QLT scattering coefficients with those found via full-orbit simulations. QLT is found to overemphasise resonance conditions. This finding supports the simplifications implemented in the presented coronal shock acceleration (CSA) simulation software. The CSA software package is used to simulate a range of acceleration scenarios. The results are found to be in agreement with well-established particle acceleration theory. At the same time, new spatial and temporal dynamics of particle population trapping and wave evolution are revealed.

Electrical status epilepticus during sleep. Continuous spikes and waves during sleep

ABSTRACT Maria Peltola Electrical status epilepticus during sleep – Continuous spikes and waves during sleep Department of Clinical Neurophysiology, University of Turku Department of Clinical Neurophysiology and Department of Pediatric Neurology, Children’s Hospital, Helsinki University Central Hospital Annales Universitatis Turkuensis, Medica-Odontologica, Turku, Finland, 2014 Background: Electrical status epilepticus during sleep (ESES) is an EEG phenomenon of frequent spikes and waves occurring in slow sleep. ESES relates to cognitive deterioration in heterogeneous childhood epilepsies. Validated methods to quantitate ESES are missing. The clinical syndrome, called epileptic encephalopathy with continuous spikes and waves during sleep (CSWS) is pharmacoresistant in half of the patients. Limited data exists on surgical treatment of CSWS. Aims and methods: The effects of surgical treatment were studied by investigating electroclinical outcomes in 13 operated patients (nine callosotomies, four resections) with pharmacoresistant CSWS and cognitive decline. Secondly, an objective paradigm was searched for assessing ESES by the semiautomatic quantification of spike index (SI) and measuring spike strength from EEG. Results: Postoperatively, cognitive deterioration was stopped in 12 (92%) patients. Three out of four patients became seizure-free after resective surgery. Callosotomy resulted in greater than 90% reduction of atypical absences in six out of eight patients. The preoperative propagation of ESES from one hemisphere to the other was associated with a good response. Semiautomatic quantification of SI was a robust method when the maximal interspike interval of three seconds was used to determine the “continuous” discharge in ten EEGs. SI of the first hour of sleep appeared representative of the whole night SI. Furthermore, the spikes’ root mean square was found to be a stable measure of spike strength when spatially integrated over multiple electrodes during steady NREM sleep. Conclusions: Patients with pharmacoresistant CSWS, based on structural etiology, may benefit from resective surgery or corpus callosotomy regarding both seizure outcome and cognitive prognosis. The semiautomated SI quantification, with proper userdefined settings and the new spatially integrated measure of spike strength, are robust and promising tools for quantifying ESES. Keywords: Electrical status epilepticus during sleep, ESES, continuous spikes and waves during sleep, CSWS, epilepsy surgery, spike index, spike strength, RMS TIIVISTELMÄ Maria Peltola Unenaikainen sähköinen status epilepticus Kliininen neurofysiologia, Turun yliopisto Kliininen neurofysiologia ja lastenneurologia, Lasten ja nuorten sairaala, Helsingin yliopistollinen keskussairaala Annales Universitatis Turkuensis, Medica-Odontologica, Turku, Suomi, 2014 Tausta: Sähköinen status epilepticus unessa (ESES) on aivosähkökäyrä (EEG)-ilmiö, jossa hidasaaltounen aikana esiintyy tiheä piikkihidasaaltopurkaus. ESES:n kvantifioimiseen ei ole olemassa validoituja menetelmiä. ESES on liitetty kognitiivisen tason laskuun ja tällöin puhutaan CSWS (continuous spikes and waves during sleep) - oireyhtymästä. CSWS ei vastaa lääkehoitoon puolella potilaista ja sen epilepsiakirurgisesta hoidosta on olemassa vain vähän tietoa. Tavoitteet ja menetelmät: Selvitimme retrospektiivisesti epilepsiakirurgian vaikusta elektrokliinisiin löydöksiin 13:lla lääkeresistenttiä CSWS-oireyhtymää sairastavalla lapsella, joilla oli rakenteellinen aivojen poikkeavuus. Toinen tavoite oli löytää objektiivinen puoliautomaattinen tapa mitata purkauksen määrää ja piikkien voimakkuutta EEG:stä. Tulokset: Kognitiivisen tason jatkuva heikentyminen loppui 12 (92 %) potilaalla leikkauksen jälkeen. Kolme neljästä resektiopotilaasta tuli kohtauksettomaksi. Kallosotomian jälkeen kuudella kahdeksasta potilaasta päivittäiset kohtaukset vähenivät yli 90 %:lla. Purkauksen leviäminen leikkausta edeltävästi vain yhdestä hemisfääristä toiseen liittyi hyvään leikkaushoitovasteeseen. Piikki-indeksi, jossa käytetään jatkuvan purkauksen määritelmänä maksimissaan kolmea sekuntia piikkien välillä, osoittautui luotettavaksi menetelmäksi ESES:n kvantifioimiseen. Useammasta elektrodista integroitu piikkien neliöllinen keskiarvo oli piikin voimakkuuden vakaa mitta häiriintymättömässä NREM-unessa. Päätelmät: Lääkehoidolle vastaamatonta CSWS:ää sairastavat potilaat, joilla on rakenteellinen aivopoikkeavuus ja yhdensuuntainen purkauksen leviämismalli, näyttävät kohtausten vähenemisen lisäksi hyötyvän epilepsiakirurgiasta kognitiivisesti. Puoliautomaattinen piikki-indeksin kvantifiointi sopivilla käyttäjäasetuksilla ja uusi spatiaalisesti integroitu piikin voimakkuuden mittari ovat stabiileja ja lupaavia ESES:n kvantitatiivisia mittareita. Avainsanat: Unenaikainen sähköinen status epilepticus, ESES, CSWS, epilepsiakirurgia, piikki-indeksi, piikin voimakkuus, neliöllinen keskiarvo

Choosing the target loci : heat shock factors HSF1 and HSF2 as regulators of cell stress and development

Heat shock factors (HSFs) are an evolutionarily well conserved family of transcription factors that coordinate stress-induced gene expression and direct versatile physiological processes in eukaryote organisms. The essentiality of HSFs for cellular homeostasis has been well demonstrated, mainly through HSF1-induced transcription of heat shock protein (HSP) genes. HSFs are important regulators of many fundamental processes such as gametogenesis, metabolic control and aging, and are involved in pathological conditions including cancer progression and neurodegenerative diseases. In each of the HSF-mediated processes, however, the detailed mechanisms of HSF family members and their complete set of target genes have remained unknown. Recently, rapid advances in chromatin studies have enabled genome-wide characterization of protein binding sites in a high resolution and in an unbiased manner. In this PhD thesis, these novel methods that base on chromatin immunoprecipitation (ChIP) are utilized and the genome-wide target loci for HSF1 and HSF2 are identified in cellular stress responses and in developmental processes. The thesis and its original publications characterize the individual and shared target genes of HSF1 and HSF2, describe HSF1 as a potent transactivator, and discover HSF2 as an epigenetic regulator that coordinates gene expression throughout the cell cycle progression. In male gametogenesis, novel physiological functions for HSF1 and HSF2 are revealed and HSFs are demonstrated to control the expression of X- and Y-chromosomal multicopy genes in a silenced chromatin environment. In stressed human cells, HSF1 and HSF2 are shown to coordinate the expression of a wide variety of genes including genes for chaperone machinery, ubiquitin, regulators of cell cycle progression and signaling. These results highlight the importance of cell type and cell cycle phase in transcriptional responses, reveal the myriad of processes that are adjusted in a stressed cell and describe novel mechanisms that maintain transcriptional memory in mitotic cell division.

Thalidomide protects mice against LPS-induced shock

Thalidomide has been shown to selectively inhibit TNF-a production in vitro by lipopolysaccharide (LPS)-stimulated monocytes. TNF-a has been shown to play a pivotal role in the pathophysiology of endotoxic shock. Using a mouse model of LPS-induced shock, we investigated the effects of thalidomide on the production of TNF-a and other cytokines and on animal survival. After injection of 100-350 µg LPS into mice, cytokines including TNF-a, IL-6, IL-10, IL-1ß, GM-CSF and IFN-g were measured in the serum. Administration of 200 mg/kg thalidomide to mice before LPS challenge modified the profile of LPS-induced cytokine secretion. Serum TNF-a levels were reduced by 93%, in a dose-dependent manner, and TNF-a mRNA expression in the spleens of mice was reduced by 70%. Serum IL-6 levels were also inhibited by 50%. Thalidomide induced a two-fold increase in serum IL-10 levels. Thalidomide treatment did not interfere with the production of GM-CSF, IL-1ß or IFN-g. The LD50 of LPS in this model was increased by thalidomide pre-treatment from 150 µg to 300 µg in 72 h. Thus, at otherwise lethal doses of LPS, thalidomide treatment was found to protect animals from death

Acetylcholinesterase activity in the pons and medulla oblongata of rats after chronic electroconvulsive shock

An imbalance between cholinergic and noradrenergic neurotransmission has been proposed for the etiology of affective disorders. According to this hypothesis, depression would be the result of enhanced cholinergic and reduced noradrenergic neurotransmission. Repeated electroconvulsive shock (ECS) is an effective treatment for depression; moreover, in laboratory animals it induces changes in brain noradrenergic neurotransmission similar to those obtained by chronic treatment with antidepressant drugs (down-regulation of beta-adrenergic receptors). The aim of the present study was to determine whether repeated ECS in rats changes acetylcholinesterase (Achase) activity. Achase controls the level of acetylcholine (Ach) in the synaptic cleft and its levels seem to be regulated by the interaction between Ach and its receptor. Thus, a decrease in Achase activity would suggest decreased cholinergic activity. Adult male Wistar rats received one ECS (80 mA, 0.2 s, 60 Hz) daily for 7 days. Control rats were handled in the same way without receiving the shock. Rats were sacrificed 24 h after the last ECS and membrane-bound and soluble Achase activity was assayed in homogenates obtained from the pons and medulla oblongata. A statistically significant decrease in membrane-bound Achase activity (nmol thiocholine formed min-1 mg protein-1) (control 182.6 ± 14.8, ECS 162.2 ± 14.2, P<0.05) and an increase in soluble Achase activity in the medulla oblongata (control 133.6 ± 4.2, ECS 145.8 ± 12.3, P<0.05) were observed. No statistical differences were observed in Achase activity in the pons. Although repeated ECS induced a decrease in membrane-bound Achase activity, the lack of changes in the pons (control Achase activity: total 231.0 ± 34.5, membrane-bound 298.9 ± 18.5, soluble 203.9 ± 30.9), the region where the locus coeruleus, the main noradrenergic nucleus, is located, does not seem to favor the existence of an interaction between cholinergic and noradrenergic neurotransmission after ECS treatment

Anterograde effects of a single electroconvulsive shock on inhibitory avoidance and on cued fear conditioning

A single electroconvulsive shock (ECS) or a sham ECS was administered to male 3-4-month-old Wistar rats 1, 2, and 4 h before training in an inhibitory avoidance test and in cued classical fear conditioning (measured by means of freezing time in a new environment). ECS impaired inhibitory avoidance at all times and, at 1 or 2 h before training, reduced freezing time before and after re-presentation of the ECS. These results are interpreted as a transient conditioned stimulus (CS)-induced anxiolytic or analgesic effect lasting about 2 h after a single treatment, in addition to the known amnesic effect of the stimulus. This suggests that the effect of anterograde learning impairment is demonstrated unequivocally only when the analgesic/anxiolytic effect is over (about 4 h after ECS administration) and that this impairment of learning is selective, affecting inhibitory avoidance but not classical fear conditioning to a discrete stimulus.

Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

To investigate the role of nitric oxide in human sepsis, ten patients with severe septic shock requiring vasoactive drug therapy and mechanical ventilation were enrolled in a prospective, open, non-randomized clinical trial to study the acute effects of methylene blue, an inhibitor of guanylate cyclase. Hemodynamic and metabolic variables were measured before and 20, 40, 60, and 120 min after the start of a 1-h intravenous infusion of 4 mg/kg of methylene blue. Methylene blue administration caused a progressive increase in mean arterial pressure (60 [55-70] to 70 [65-100] mmHg, median [25-75th percentiles]; P<0.05), systemic vascular resistance index (649 [479-1084] to 1066 [585-1356] dyne s-1 cm-5 m-2; P<0.05) and the left ventricular stroke work index (35 [27-47] to 38 [32-56] g m-1 m-2; P<0.05) from baseline to 60 min. The pulmonary vascular resistance index increased from 150 [83-207] to 186 [121-367] dyne s-1 cm-5 m-2 after 20 min (P<0.05). Mixed venous saturation decreased from 65 [56-76] to 63 [55-69]% (P<0.05) after 60 min. The PaO2/FiO2 ratio decreased from 168 [131-215] to 132 [109-156] mmHg (P<0.05) after 40 min. Arterial lactate concentration decreased from 5.1 ± 2.9 to 4.5 ± 2.1 mmol/l, mean ± SD (P<0.05) after 60 min. Heart rate, cardiac filling pressures, cardiac output, oxygen delivery and consumption did not change. Methylene blue administration was safe and no adverse effect was observed. In severe human septic shock, a short infusion of methylene blue increases systemic vascular resistance and may improve myocardial function. Although there was a reduction in blood lactate concentration, this was not explained by an improvement in tissue oxygenation, since overall oxygen availability did not change. However, there was a significant increase in pulmonary vascular tone and a deterioration in gas exchange. Further studies are needed to demonstrate if nitric oxide blockade with methylene blue can be safe for patients with septic shock and, particularly, if it has an effect on pulmonary function.

Compound 48/80, a histamine-depleting agent, blocks the protective effect of morphine against electroconvulsive shock in mice

We have shown that morphine has an anticonvulsive effect against maximal electroconvulsive shock (MES) in mice, and this effect is antagonized by histamine H1-receptor antagonists. Brain histamine is localized both in neurons and in mast cells, and morphine is known to enhance the turnover of neuronal histamine and to release histamine from mast cells. In the present experiments, compound 48/80 was injected chronically (0.5 mg/kg on day 1, 1 mg/kg on day 2, 2 mg/kg on day 3, 3 mg/kg on day 4, and 4 mg/kg on day 5, twice daily, ip) to deplete mast cell contents. Morphine (0.001-10 mg/kg, ip; N = 20) produced a dose-dependent anticonvulsive effect against MES seizure in mice with non-depleted mast cells, whereas it did not exert any anticonvulsive effect in mice with depleted mast cells. These results indicate that morphine produces its anticonvulsive effect against maximal electroconvulsive shock in mice by liberating histamine from mast cells.