Function and regulation of Cdk7

Understanding the process of cell division is crucial for modern cancer medicine due to the central role of uncontrolled cell division in this disease. Cancer involves unrestrained proliferation as a result of cells loosing normal control and being driven through the cell cycle, where they normally would be non-dividing or quiescent. Progression through the cell cycle is thought to be dependent on the sequential activation of cyclin-dependent kinases (Cdks). The full activation of Cdks requires the phosphorylation of a conserved residue (threonine-160 on human Cdk2) on the T-loop of the kinase domain. In metazoan species, a trimeric complex consisting of Cdk7, cyclin H and Mat1 has been suggested to be the T-loop kinase of several Cdks. In addition, Cdk7 have also been implicated in the regulation of transcription. Cdk7, cyclin H, and Mat1 can be found as subunits of general transcription factor TFIIH. Cdk7, in this context, phosphorylates the Carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (RNA pol II), specifically on serine-5 residues of the CTD repeat. The regulation of Cdk7 in these and other functions is not well known and the unambiguous characterization of the in vivo role of Cdk7 in both T-loop activation and CTD serine-5 phosphorylation has proved challenging. In this study, the fission yeast Cdk7-cyclin H homologous complex, Mcs6-Mcs2, is identified as the in vivo T-loop kinase of Cdk1(Cdc2). It also identifies multiple levels of regulation of Mcs6 kinase activity, i.e. association with Pmh1, a novel fission yeast protein that is the apparent homolog of metazoan Mat1, and T-loop phosphorylation of Mcs6, mediated by Csk1, a monomeric T-loop kinase with similarity to Cak1 of budding yeast. In addition, Skp1, a component of the SCF (Skp1-Cullin-F box protein) ubiquitin ligase is identified by its interactions with Mcs2 and Pmh1. The Skp1 association with Mcs2 and Pmh1 is however SCF independent and does not involve proteolytic degradation but may reflect a novel mechanism to modulate the activity or complex assembly of Mcs6. In addition to Cdk7, also Cdk8 has been shown to have CTD serine-5 kinase activity in vitro. Cdk8 is not essential in yeast but has been shown to function as a transcriptional regulator. The function of Cdk8 is unknown in flies and mammals. This prompted the investigation of murine Cdk8 and its potential role as a redundant CTD serine-5 kinase. We find that Cdk8 is required for development prior to implantation, at a time that is co-incident with a burst of Cdk8 expression during normal development. The results does not support a role of Cdk8 as a serine-5 CTD kinase in vivo but rather shows an unexpected requirement for Cdk8, early in mammalian development. The results presented in this thesis extends our current knowledge of the regulation of the cell cycle by characterizing the function of two distinct cell cycle regulating T-loop kinases, including the unambiguous identification of Mcs6, the fission yeast Cdk7 homolog, as the T-loop kinase of Cdk1. The results also indicate that the function of Mcs6 is conserved from fission yeast to human Cdk7 and suggests novel mechanisms by which the distinct functions of Cdk7 and Mcs6 could be regulated. These findings are important for our understanding of how progression of the cell cycle and proper transcription is controlled, during normal development and tissue homeostasis but also under condition where cells have escaped these control mechanisms e.g. cancer.

Generalized Burgers equations and Euler-Painlev transcendents. I

Initial-value problems for the generalized Burgers equation (GBE) ut+u betaux+lambdaualpha =(delta/2)uxx are discussed for the single hump type of initial data both continuous and discontinuous. The numerical solution is carried to the self-similar ``intermediate asymptotic'' regime when the solution is given analytically by the self-similar form. The nonlinear (transformed) ordinary differential equations (ODE's) describing the self-similar form are generalizations of a class discussed by Euler and Painlevé and quoted by Kamke. These ODE's are new, and it is postulated that they characterize GBE's in the same manner as the Painlev equations categorize the Kortweg-de Vries (KdV) type. A connection problem for some related ODE's satisfying proper asymptotic conditions at x=±[infinity], is solved. The range of amplitude parameter is found for which the solution of the connection problem exists. The other solutions of the above GBE, which display several interesting features such as peaking, breaking, and a long shelf on the left for negative values of the damping coefficient lambda, are also discussed. The results are compared with those holding for the modified KdV equation with damping. Journal of Mathematical Physics is copyrighted by The American Institute of Physics.

Tuning of PID controllers for water networks—different approaches

Better operational control of water networks can help reduce leakage, maintain pressure, and control flow. Proportional integral derivative (PID) controllers, with proper fine-tuning, can help water utility operators achieve targets faster without creating undue transients. The authors compared three tuning methods, in different test situations, involving flow and level control to different reservoirs. Although target values were reached with all three tuning methods, the methods’ performances varied significantly. The lowest performer among the three was the method most widely used in the industry—standard tuning by the Ziegler-Nichols method. Achieving better results was offline tuning by genetic algorithms. Achieving the best control, though, was a fuzzy logic–based online tuning approach—the FZPID controller. The FZPID controller had fewer overshoots and took significantly less time to tune the gains for each problem. This new tuning approach for PID controllers can be applied to a variety of problems and can increase the performance of water networks of any size and structure

On the axiomatic approach to the maximum entropy principle of inference

Recent axiomatic derivations of the maximum entropy principle from consistency conditions are critically examined. We show that proper application of consistency conditions alone allows a wider class of functionals, essentially of the form ∝ dx p(x)[p(x)/g(x)] s , for some real numbers, to be used for inductive inference and the commonly used form − ∝ dx p(x)ln[p(x)/g(x)] is only a particular case. The role of the prior densityg(x) is clarified. It is possible to regard it as a geometric factor, describing the coordinate system used and it does not represent information of the same kind as obtained by measurements on the system in the form of expectation values.

High-density lipoprotein 17beta-estradiol fatty acyl esters and phytoestrogens : Impact on reverse cholesterol transport and women's cardiovascular health

Reverse cholesterol transport (RCT) is an important function of high-density lipoproteins (HDL) in the protection of atherosclerosis. RCT is the process by which HDL stimulates cholesterol removal from peripheral cells and transports it to the liver for excretion. Premenopausal women have a reduced risk for atherosclerosis compared to age-matched men and there exists a positive correlation for serum 17β-estradiol (E2) and HDL levels in premenopausal women supporting the role of E2 in atherosclerosis prevention. In premenopausal women, E2 associates with HDL as E2 fatty acyl esters. Discovery of the cellular targets, metabolism, and assessment of the macrophage cholesterol efflux potential of these HDL-associated E2 fatty acyl esters were the major objectives of this thesis (study I, III, and IV). Soy phytoestrogens, which are related to E2 in both structure and function, have been proposed to be protective against atherosclerosis but the evidence to support these claims is conflicting. Therefore, another objective of this thesis was to assess the ability of serum from postmenopausal women, treated with isoflavone supplements (compared to placebo), to promote macrophage cholesterol efflux (study II). The scope of this thesis was to cover the roles that HDL-associated E2 fatty acyl esters have in the cellular aspects of RCT and to determine if soy isoflavones can also influence RCT mechanisms. SR-BI was a pivotal cellular receptor, responsible for hepatic and macrophage uptake and macrophage cholesterol efflux potential of HDL-associated E2 fatty acyl esters. Functional SR-BI was also critical for proper LCAT esterification activity which could impact HDL-associated E2 fatty acyl ester assembly and its function. In hepatic cells, LDL receptors also contributed to HDL-associated E2 fatty acyl esters uptake and in macrophage cells, estrogen receptors (ERs) were necessary for both HDL-associated E2 ester-specific uptake and cholesterol efflux potential. HDL-containing E2 fatty acyl esters (E2-FAE) stimulated enhanced cholesterol efflux compared to male HDL (which are deficient in E2) demonstrating the importance of the E2 ester in this process. To support this, premenopausal female HDL, which naturally contains E2, showed greater macrophage cholesterol efflux compared to males. Additionally, hepatic and macrophage cells hydrolyzed the HDL-associated E2 fatty acyl ester into unesterified E2. This could have important biological ramifications because E2, not the esterified form, has potent cellular effects which may influence RCT mechanisms. Lastly, soy isoflavone supplementation in postmenopausal women did not modulate ABCA1-specific macrophage cholesterol efflux but did increase production of plasma pre-β HDL levels, a subclass of HDL. Therefore, the impact of isoflavones on RCT and cardiovascular health needs to be further investigated. Taken as a whole, HDL-associated E2 fatty acyl esters from premenopausal women and soy phytoestrogen treatment in postmenopausal women may be important factors that increase the efficiency of RCT through cellular lipoprotein-related processes and may have direct implications on the cardiovascular health of women.

A Newton-Euler formulation for the inverse dynamics of the Stewart platform manipulator

This paper presents an inverse dynamic formulation by the Newton–Euler approach for the Stewart platform manipulator of the most general architecture and models all the dynamic and gravity effects as well as the viscous friction at the joints. It is shown that a proper elimination procedure results in a remarkably economical and fast algorithm for the solution of actuator forces, which makes the method quite suitable for on-line control purposes. In addition, the parallelism inherent in the manipulator and in the modelling makes the algorithm quite efficient in a parallel computing environment, where it can be made as fast as the corresponding formulation for the 6-dof serial manipulator. The formulation has been implemented in a program and has been used for a few trajectories planned for a test manipulator. Results of simulation presented in the paper reveal the nature of the variation of actuator forces in the Stewart platform and justify the dynamic modelling for control.

Prevention of type 2 diabetes with lifestyle intervention - emphasis on dietary composition and identification of high-risk individuals

Type 2 diabetes is an increasing, serious, and costly public health problem. The increase in the prevalence of the disease can mainly be attributed to changing lifestyles leading to physical inactivity, overweight, and obesity. These lifestyle-related risk factors offer also a possibility for preventive interventions. Until recently, proper evidence regarding the prevention of type 2 diabetes has been virtually missing. To be cost-effective, intensive interventions to prevent type 2 diabetes should be directed to people at an increased risk of the disease. The aim of this series of studies was to investigate whether type 2 diabetes can be prevented by lifestyle intervention in high-risk individuals, and to develop a practical method to identify individuals who are at high risk of type 2 diabetes and would benefit from such an intervention. To study the effect of lifestyle intervention on diabetes risk, we recruited 522 volunteer, middle-aged (aged 40 - 64 at baseline), overweight (body mass index > 25 kg/m2) men (n = 172) and women (n = 350) with impaired glucose tolerance to the Diabetes Prevention Study (DPS). The participants were randomly allocated either to the intensive lifestyle intervention group or the control group. The control group received general dietary and exercise advice at baseline, and had annual physician's examination. The participants in the intervention group received, in addition, individualised dietary counselling by a nutritionist. They were also offered circuit-type resistance training sessions and were advised to increase overall physical activity. The intervention goals were to reduce body weight (5% or more reduction from baseline weight), limit dietary fat (< 30% of total energy consumed) and saturated fat (< 10% of total energy consumed), and to increase dietary fibre intake (15 g / 1000 kcal or more) and physical activity (≥ 30 minutes/day). Diabetes status was assessed annually by a repeated 75 g oral glucose tolerance testing. First analysis on end-points was completed after a mean follow-up of 3.2 years, and the intervention phase was terminated after a mean duration of 3.9 years. After that, the study participants continued to visit the study clinics for the annual examinations, for a mean of 3 years. The intervention group showed significantly greater improvement in each intervention goal. After 1 and 3 years, mean weight reductions were 4.5 and 3.5 kg in the intervention group and 1.0 kg and 0.9 kg in the control group. Cardiovascular risk factors improved more in the intervention group. After a mean follow-up of 3.2 years, the risk of diabetes was reduced by 58% in the intervention group compared with the control group. The reduction in the incidence of diabetes was directly associated with achieved lifestyle goals. Furthermore, those who consumed moderate-fat, high-fibre diet achieved the largest weight reduction and, even after adjustment for weight reduction, the lowest diabetes risk during the intervention period. After discontinuation of the counselling, the differences in lifestyle variables between the groups still remained favourable for the intervention group. During the post-intervention follow-up period of 3 years, the risk of diabetes was still 36% lower among the former intervention group participants, compared with the former control group participants. To develop a simple screening tool to identify individuals who are at high risk of type 2 diabetes, follow-up data of two population-based cohorts of 35-64 year old men and women was used. The National FINRISK Study 1987 cohort (model development data) included 4435 subjects, with 182 new drug-treated cases of diabetes identified during ten years, and the FINRISK Study 1992 cohort (model validation data) included 4615 subjects, with 67 new cases of drug-treated diabetes during five years, ascertained using the Social Insurance Institution's Drug register. Baseline age, body mass index, waist circumference, history of antihypertensive drug treatment and high blood glucose, physical activity and daily consumption of fruits, berries or vegetables were selected into the risk score as categorical variables. In the 1987 cohort the optimal cut-off point of the risk score identified 78% of those who got diabetes during the follow-up (= sensitivity of the test) and 77% of those who remained free of diabetes (= specificity of the test). In the 1992 cohort the risk score performed equally well. The final Finnish Diabetes Risk Score (FINDRISC) form includes, in addition to the predictors of the model, a question about family history of diabetes and the age category of over 64 years. When applied to the DPS population, the baseline FINDRISC value was associated with diabetes risk among the control group participants only, indicating that the intensive lifestyle intervention given to the intervention group participants abolished the diabetes risk associated with baseline risk factors. In conclusion, the intensive lifestyle intervention produced long-term beneficial changes in diet, physical activity, body weight, and cardiovascular risk factors, and reduced diabetes risk. Furthermore, the effects of the intervention were sustained after the intervention was discontinued. The FINDRISC proved to be a simple, fast, inexpensive, non-invasive, and reliable tool to identify individuals at high risk of type 2 diabetes. The use of FINDRISC to identify high-risk subjects, followed by lifestyle intervention, provides a feasible scheme in preventing type 2 diabetes, which could be implemented in the primary health care system.

Shift in disease burden from communicable to non-communicable diseases: Aiming to achieve Universal Health Coverage in Nepal

A major barrier to accessing healthcare services is spending, and the extended time that non-communicable diseases require treatment for means that many people around the world do not have proper access to care. Saval Khanal from Sankalpa Foundation, Nepal, Lennert Veerman and Samantha Hollingworth from the University of Queensland and Lisa Nissen from Queensland University of Technology lay out the results of their study and establish a method to forecast medicine use in Nepal.

Probing into the role of conserved N-glycosylation sites in the Tyrosinase glycoprotein family

N-linked glycosylation has a profound effect on the proper folding, oligomerization and stability of glycoproteins. These glycans impart many properties to proteins that may be important for their proper functioning, besides having a tendency to exert a chaperone-like effect on them. Certain glycosylation sites in a protein however, are more important than other sites for their function and stability. It has been observed that some N-glycosylation sites are conserved over families of glycoproteins over evolution, one such being the tyrosinase related protein family. The role of these conserved N-glycosylation sites in their trafficking, sorting, stability and activity has been examined here. By scrutinizing the different glycosylation sites on this family of glycoproteins it was inferred that different sites in the same family of polypeptides can perform distinct functions and conserved sites across the paralogues may perform diverse functions.

Genetic basis of hereditary colorectal cancers: Hereditary nonpolyposis colorectal cancer and Familial adenomatous polyposis

Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) are characterized by a high risk and early onset of colorectal cancer (CRC). HNPCC is due to a germline mutation in one of the following MMR genes: MLH1, MSH2, MSH6 and PMS2. A majority of FAP and attenuated FAP (AFAP) cases are due to germline mutations of APC, causing the development of multiple colorectal polyps. To date, over 450 MMR gene mutations and over 800 APC mutations have been identified. Most of these mutations lead to a truncated protein, easily detected by conventional mutation detection methods. However, in about 30% of HNPCC and FAP, and about 90% of AFAP families, mutations remain unknown. We aimed to clarify the genetic basis and genotype-phenotype correlation of mutation negative HNPCC and FAP/AFAP families by advanced mutation detection methods designed to detect large genomic rearrangements, mRNA and protein expression alterations, promoter mutations, phenotype linked haplotypes, and tumoral loss of heterozygosity. We also aimed to estimate the frequency of HNPCC in Uruguayan CRC patients. Our expression based analysis of mutation negative HNPCC divided these families into two categories: 1) 42% of families linked to the MMR genes with a phenotype resembling that of mutation positive, and 2) 58% of families likely to be associated with other susceptibility genes. Unbalanced mRNA expression of MLH1 was observed in two families. Further studies revealed that a MLH1 nonsense mutation, R100X was associated with aberrant splicing of exons not related to the mutation and an MLH1 deletion (AGAA) at nucleotide 210 was associated with multiple exon skipping, without an overall increase in the frequency of splice events. APC mutation negative FAP/AFAP families were divided into four groups according to the genetic basis of their predisposition. Four (14%) families displayed a constitutional deletion of APC with profuse polyposis, early age of onset and frequent extracolonic manifestations. Aberrant mRNA expression of one allele was observed in seven (24%) families with later onset and less frequent extracolonic manifestations. In 15 (52%) families the involvement of APC could neither be confirmed nor excluded. In three (10%) of the families a germline mutation was detected in genes other than APC: AXIN2 in one family, and MYH in two families. The families with undefined genetic basis and especially those with AXIN2 or MYH mutations frequently displayed AFAP or atypical polyposis. Of the Uruguayan CRC patients, 2.6% (12/461) fulfilled the diagnostic criteria for HNPCC and 5.6% (26/461) were associated with increased risk of cancer. Unexpectedly low frequency of molecularly defined HNPCC cases may suggest a different genetic profile in the Uruguayan population and the involvement of novel susceptibility genes. Accurate genetic and clinical characterization of families with hereditary colorectal cancers, and the definition of the genetic basis of "mutation negative" families in particular, facilitate proper clinical management of such families.

VEGF-C/VEGFR-3 and PDGF-B/PDGFR-b pathways in embryonic lymphangiogenesis

The circulatory system comprises the blood vascular system and the lymphatic vascular system. These two systems function in parallel. Blood vessels form a closed system that delivers oxygen and nutrients to the tissues and removes waste products from the tissues, while lymphatic vessels are blind-ended tubes that collect extravasated fluid and cells from the tissues and return them back to blood circulation. Development of blood and lymphatic vascular systems occurs in series. Blood vessels are formed via vasculogenesis and angiogenesis whereas lymphatic vessels develop via lymphangiogenesis, after the blood vascular system is already functional. Members of the vascular endothelial growth factor (VEGF) family are regulators of both angiogenesis and lymphangiogenesis, while members of the platelet-derived growth factor (PDGF) family are major mitogens for pericytes and smooth muscle cells and regulate formation of blood vessels. Vascular endothelial growth factor C (VEGF-C) is the major lymphatic growth factor and signaling through its receptor vascular endothelial growth factor receptor 3 (VEGFR-3) is sufficient for lymphangiogenesis in adults. We studied the role of VEGF-C in embryonic lymphangiogenesis and showed that VEGF-C is absolutely required for the formation of lymph sacs from embryonic veins. VEGFR-3 is also required for normal development of the blood vascular system during embryogenesis, as Vegfr3 knockout mice die at mid-gestation due to failure in remodeling of the blood vessels. We showed that sufficient VEGFR-3 signaling in the embryo proper is required for embryonic angiogenesis and in a dosage-sensitive manner for embryonic lymphangiogenesis. Importantly, mice deficient in both VEGFR-3 ligands, Vegfc and Vegfd, developed a normal blood vasculature, suggesting VEGF-C- and VEGF-D- independent functions for VEGFR-3 in the early embryo. Platelet-derived growth factor B (PDGF-B) signals via PDGFR-b and regulates formation of blood vessels by recruiting pericytes and smooth muscle cells around nascent endothelial tubes. We showed that PDGF-B fails to induce lymphangiogenesis when overexpressed in adult mouse skin using adenoviral vectors. However, mouse embryos lacking Pdgfb showed abnormal lymphatic vessels, suggesting that PDGF-B plays a role in lymphatic vessel maturation and separation from blood vessels during embryogenesis. Lymphatic vessels play a key role in immune surveillance, fat absorption and maintenance of fluid homeostasis in the body. However, lymphatic vessels are also involved in various diseases, such as lymphedema and tumor metastasis. These studies elucidate the basic mechanisms of embryonic lymphangiogenesis and add to the knowledge of lymphedema and tumor metastasis treatments by giving novel insights into how lymphatic vessel growth could be induced (in lymphedema) or inhibited (in tumor metastasis).

Molecular biology of progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1)

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited disorder characterized by age of onset at 6-15 years, stimulus-sensitive myoclonus, tonic-clonic epileptic seizures and a progressive course. Mutations in the cystatin B (CSTB) gene underlie EPM1. The most common mutation underlying EPM1 is a dodecamer repeat expansion in the promoter region of CSTB. In addition, nine other mutations have been identified. CSTB, a cysteine protease inhibitor, is a ubiquitously expressed inhibitor of cathepsins, but its physiological function is unknown. The purpose of this study was to investigate CSTB gene expression and CSTB protein function in normal and pathological conditions. The basal CSTB promoter was mapped and characterized using different promoter-luciferase gene constructs. The binding activity of transcription factors to one ARE half, five Sp1 and four AP1 sites in the CSTB promoter was demonstrated. The CSTB promoter activity was clearly decreased using a CSTB promoter with "premutation" repeat expansions and in individuals with alike expansions. The expression of CSTB mRNA and protein was markedly reduced in patient cells. The endogenous CSTB protein localized to the nucleus, cytoplasm and lysosomes, and in differentiated cells merely to the cytoplasm. This suggests that the subcellular distribution of CSTB is dependent on the differentation status of the cells. The proteins representing patient missense mutations failed to associate with lysosomes, implying the importance of the lysosomal association for the proper physiological function of CSTB. Several alternatively spliced CSTB isoforms were identified. Of these CSTB2 was widely expressed with very low levels whereas the other alternatively spliced forms seemed to have limited tissue expression. In patients CSTB2 expression was reduced similarly to that of CSTB. The physiological relevance of CSTB alternative splicing remains unknown. The mouse Cstb transcript was shown to be present in all embryonic stages and adult tissues examined. The expression was highest at embryonic day 7 and in thymus, as well as in postnatal brain in the cortex, caudate putamen, thalamus, hippocampus, and in the Purkinje cell layer of the cerebellum. Our data implies that CSTB expression is tightly temporally and spatially regulated. The data presented in my thesis lay the basis for further understanding of the role of CSTB in health and disease.

Searching for common threads in threadfins: phylogeography of Australian polynemids in space and time

Proper management of marine fisheries requires an understanding of the spatial and temporal dynamics of marine populations, which can be obtained from genetic data. While numerous fisheries species have been surveyed for spatial genetic patterns, temporally sampled genetic data is not available for many species. We present a phylogeographic survey of the king threadfin Polydactylus macrochir across its species range in northern Australia and at a temporal scale of 1 and 10 yr. Spatially, the overall AMOVA fixation index was Omega(st) = 0.306 (F-st' = 0.838), p < 0.0001 and isolation by distance was strong and significant (r(2) = 0.45, p < 0.001). Temporally, genetic patterns were stable at a time scale of 10 yr. However, this did not hold true for samples from the eastern Gulf of Carpentaria, where populations showed a greater degree of temporal instability and lacked spatial genetic structure. Temporal but not spatial genetic structure in the Gulf indicates demographic interdependence but also indicates that fishing pressure may be high in this area. Generally, genetic patterns were similar to another co-distributed threadfin species Eleutheronema tetradactylum, which is ecologically similar. However, the historical demography of both species, evaluated herein, differed, with populations of P. macrochir being much younger. The data are consistent with an acute population bottleneck at the last glacio-eustatic low in sea level and indicate that the king threadfin may be sensitive to habitat disturbances.

Äidinmaito - terveysjuomaa ja normaalibakteereita

The chemical composition of breast milk has been studied in detail in the past decades. Hundreds of new antibacterial and antiviral components have been found. Several molecules have been found to promote the proper function of neonatal intestine. However, microbiological studies of breast milk have been, until recently, focused mainly on detecting harmful and pathogenic bacteria and viruses. Natural microbial diversity of human milk has not been widely studied before the work reported in this thesis. This is mainly because breast milk has traditionally been thought to be sterile - even if a certain amount of commensal bacteria have usually been detected in milk samples. The first part of this licentiate thesis contains a short literature review about the anatomy and physiology of breast feeding, human milk chemical and microbiological composition, mastitis, intestinal flora and bacteriocins. The second part reports on the experiments of the licentiate work, concentrating on the microbial diversity in the milk of healthy breast-feeding mothers, and the ability of these bacteria to produce antibacterial substances against pathogenic bacteria. The results indicate that human milk is a source of commensal bacteria for infant intestine. 509 random isolates from 40 breast milk samples were isolated and identified by 16S rRNA sequencing. Median bacterial count was about 600 colony forming units per milliliter. Over half of the isolates were staphylococci, and almost one third streptococci. The most common species were skin bacteria Staphylococcus epidermidis and oral bacteria Streptococcus salivarius and Streptococcus mitis. Lactic acid bacteria, identified as members of Lactobacillus-, Lactococcus- and Leuconostoc -genera, were found in five milk samples. Enterococci were found in three samples. A novel finding in this study is the capability of these commensal bacteria to inhibit the growth of pathogens. In 90 precent of the milk samples commensal bacteria inhibiting the growth of Staphylococcus aureus were found. In 40 precent of samples the colonies could block the growth completely. One fifth of the isolated Staph. epidermidis strains, half of Str. salivarius strains, and all lactic acid bacteria and enterococci could inhibit or block the growth of Staph. aureus. In further study also Listeria innocua- and Micrococcus luteus active isolates were found in 33 and 11 precent of milk samples (out of 140). Furthermore, two Lactococcus lactis isolates from the breast milk were shown to produce bacteriocin nisin, which is an antimicrobial molecule used as a food preservative. The importance of these human milk commensal bacteria in the development of newborn intestinal flora and immune system, as well as in preventing maternal breast infections, should be further explored.

Topological Quantum Computation - An Analysis of an Anyon Model Based on Quantum Double Symmetries

There exists various suggestions for building a functional and a fault-tolerant large-scale quantum computer. Topological quantum computation is a more exotic suggestion, which makes use of the properties of quasiparticles manifest only in certain two-dimensional systems. These so called anyons exhibit topological degrees of freedom, which, in principle, can be used to execute quantum computation with intrinsic fault-tolerance. This feature is the main incentive to study topological quantum computation. The objective of this thesis is to provide an accessible introduction to the theory. In this thesis one has considered the theory of anyons arising in two-dimensional quantum mechanical systems, which are described by gauge theories based on so called quantum double symmetries. The quasiparticles are shown to exhibit interactions and carry quantum numbers, which are both of topological nature. Particularly, it is found that the addition of the quantum numbers is not unique, but that the fusion of the quasiparticles is described by a non-trivial fusion algebra. It is discussed how this property can be used to encode quantum information in a manner which is intrinsically protected from decoherence and how one could, in principle, perform quantum computation by braiding the quasiparticles. As an example of the presented general discussion, the particle spectrum and the fusion algebra of an anyon model based on the gauge group S_3 are explicitly derived. The fusion algebra is found to branch into multiple proper subalgebras and the simplest one of them is chosen as a model for an illustrative demonstration. The different steps of a topological quantum computation are outlined and the computational power of the model is assessed. It turns out that the chosen model is not universal for quantum computation. However, because the objective was a demonstration of the theory with explicit calculations, none of the other more complicated fusion subalgebras were considered. Studying their applicability for quantum computation could be a topic of further research.