A Thermodynamically Consistent Damage Model for Advanced Composites

A continuum damage model for the prediction of damage onset and structural collapse of structures manufactured in fiber-reinforced plastic laminates is proposed. The principal damage mechanisms occurring in the longitudinal and transverse directions of a ply are represented by a damage tensor that is fixed in space. Crack closure under load reversal effects are taken into account using damage variables established as a function of the sign of the components of the stress tensor. Damage activation functions based on the LaRC04 failure criteria are used to predict the different damage mechanisms occurring at the ply level. The constitutive damage model is implemented in a finite element code. The objectivity of the numerical model is assured by regularizing the dissipated energy at a material point using Bazant’s Crack Band Model. To verify the accuracy of the approach, analyses ofcoupon specimens were performed, and the numerical predictions were compared with experimental data

Simulation of Delamination Propagation in Composites Under High-Cycle Fatigue by Means of Cohesive-Zone Models

A damage model for the simulation of delamination propagation under high-cycle fatigue loading is proposed. The basis for the formulation is a cohesive law that links fracture and damage mechanics to establish the evolution of the damage variable in terms of the crack growth rate dA/dN. The damage state is obtained as a function of the loading conditions as well as the experimentally-determined coefficients of the Paris Law crack propagation rates for the material. It is shown that by using the constitutive fatigue damage model in a structural analysis, experimental results can be reproduced without the need of additional model-specific curve-fitting parameters

Ewing sarcoma of the rib: respiratory tract infection as initial symptoms in a 14-year-old boy. Functional medical imaging findings

Ewing sarcoma or primitive neuroectodermal tumor (PNET) of bone is the second most common pediatric malignant bone tumor. The median age at diagnosis is 15 years and there is a male predilection of 1.5/1. The authors present the case of a 14-year-old boy with Ewing sarcoma situated on the left ninth rib which was being investigated for respiratory tract infection. Pleurisy is the most common misdiagnosis. Our case illustrates the importance of recognizing exceptional features when interpreting FDG PET or scintigraphy to prevent the misinterpretation of metastases as other etiologies, such as infection.

Long-term functional improvements in the 2-year treatment of schizophrenia outpatients with olanzapine long-acting injection

BACKGROUND: Little is known about the long-term changes in the functioning of schizophrenia patients receiving maintenance therapy with olanzapine long-acting injection (LAI), and whether observed changes differ from those seen with oral olanzapine. METHODS: This study describes changes in the levels of functioning among outpatients with schizophrenia treated with olanzapine-LAI compared with oral olanzapine over 2 years. This was a secondary analysis of data from a multicenter, randomized, open-label, 2-year study comparing the long-term treatment effectiveness of monthly olanzapine-LAI (405 mg/4 weeks; n=264) with daily oral olanzapine (10 mg/day; n=260). Levels of functioning were assessed with the Heinrichs-Carpenter Quality of Life Scale. Functional status was also classified as 'good', 'moderate', or 'poor', using a previous data-driven approach. Changes in functional levels were assessed with McNemar's test and comparisons between olanzapine-LAI and oral olanzapine employed the Student's t-test. RESULTS: Over the 2-year study, the patients treated with olanzapine-LAI improved their level of functioning (per Quality of Life total score) from 64.0-70.8 (P<0.001). Patients on oral olanzapine also increased their level of functioning from 62.1-70.1 (P<0.001). At baseline, 19.2% of the olanzapine-LAI-treated patients had a 'good' level of functioning, which increased to 27.5% (P<0.05). The figures for oral olanzapine were 14.2% and 24.5%, respectively (P<0.001). Results did not significantly differ between olanzapine-LAI and oral olanzapine. CONCLUSION: In this 2-year, open-label, randomized study of olanzapine-LAI, outpatients with schizophrenia maintained or improved their favorable baseline level of functioning over time. Results did not significantly differ between olanzapine-LAI and oral olanzapine.

Chelating Adsorbents in Purification of Hydrometallurgical Solutions

In this thesis, equilibrium and dynamic sorption properties of weakly basic chelating adsorbents were studied to explain removal of copper, nickel from a concentrated zinc sulfate solution in a hydrometallurgical process. Silica-supported chelating composites containing either branched poly(ethyleneimine) (BPEI) or 2-(aminomethyl)pyridine (AMP) as a functional group were used. The adsorbents are commercially available from Purity Systems Inc, USA as WP-1® and CuWRAM®, respectively. The fundamental interactions between the adsorbents, sulfuric acid and metal sulfates were studied in detail and the results were used to find the best conditions for removal of copper and nickel from an authentic ZnSO4 process solution. In particular, the effect of acid concentration and temperature on the separation efficiency was considered. Both experimental and modeling aspectswere covered in all cases. Metal sorption is considerably affected by the chemical properties of the studied adsorbents and by the separation conditions. In the case of WP-1, acid affinity is so high that column separation of copper, nickel and zinc has to be done using the adsorbent in base-form. On the other hand, the basicity of CuWRAM is significantly lower and protonated adsorbent can be used. Increasing temperature decreases the basicity and the metals affinity of both adsorbents, but the uptake capacities remain practically unchanged. Moreover, increasing temperature substantially enhances intra-particle mass transport and decreases viscosities thus allowing significantly higher feed flow rates in the fixed-bed separation. The copper selectivity of both adsorbents is very high even in the presence of a 250-fold excess of zinc. However, because of the basicity of WP-1, metal precipitation is a serious problem and therefore only CuWRAM is suitable for the practical industrial application. The optimum temperature for copper removal appears to be around 60 oC and an alternative solution purification method is proposed. The Ni/Zn selectivity of both WP-1 and CuWRAM is insufficient for removal of the very small amounts of nickel present in the concentrated ZnSO4 solution.

Foodstuffs and medicines as legal categories in the EU and China. Functional foods as a borderline case

The thesis discusses the regulation of foodstuffs and medicines, and particularly the regulation of functional foods. Legal systems investigated are the EU and China. Both are members of the WTO and Codex Alimentarius, which binds European and Chinese rules together. The study uses three Chinese berries as case examples of how product development faces regulation in practice. The berries have traditional uses as herbal medicines. Europe and China have similar nutrition problems to be resolved, such as obesity, cardiovascular disease, and diabetes. The three berries might be suitable raw materials for functional foods. Consumer products with health-enhancing functions, such as lowering blood pressure, might legally be classifi ed either as foodstuffs or medicines. The classifi cation will depend on functions and presentation of the product. In our opinion, food and medicine regulation should come closer together so the classifi cation issue would no longer be an issue. Safety of both foodstuffs and medicines is strictly regulated. With medicines, safety is a more relative concept, where benefi ts of the product are compared to side-effects in thorough scientifi c tests and trials. Foods, on the other hand, are not allowed to have side-effects. Hygiene rules and rules on the use of chemicals apply. In China, food safety is currently at focus as China has had several severe food scandals. Newly developed foods are called novel foods, and are specifi cally regulated. The current European novel food regulation from 1997 treats traditional third country products as novel. The Chinese regulation of 2007 also defi nes novel foods as something unfamiliar to a Chinese consumer. The concepts of novel food thus serve a protectionist purpose. As regards marketing, foods are allowed to bear health claims, whereas medicines bear medicinal claims. The separation is legally strict: foods are not to be presented as having medicinal functions. European nutrition and health claim regulation exists since 2006. China also has its regulation on health foods, listing the permitted claims and how to substantiate them. Health claims are allowed only on health foods. The European rules on medicines include separate categories for herbal medicines, traditional herbal medicines, and homeopathic medicines, where there are differing requirements for scientifi c substantiation. The scientifi c and political grounds for the separate categories provoke criticism. At surface, the Chinese legal system seems similar to the European one. To facilitate trade, China has enacted modern laws. Laws are needed as the country moves from planned economy to market economy: ‘rule of law’ needs to replace ‘rule of man’. Instead of being citizens, Chinese people long were subordinates to the Emperor. Confucius himself advised to avoid confl ict. Still, Chinese people do not and cannot always trust the legal system, as laws are enforced in an inconsistent manner, and courts are weak. In China, there have been problems with confl icting national and local laws. In Europe, the competence of the EU vs. the competence of the Member States is still not resolved, even though the European Commission often states that free trade requires harmonisation. Food and medicine regulation is created by international organisations, food and medicine control agencies, standards agencies, companies and their organisations. Regulation can be divided in ‘hard law’ and ‘soft law’. One might claim that hard law is in crisis, as soft law is gaining importance. If law is out of fashion, regulation certainly isn’t. In the future, ‘law’ might mean a process where rules and incentives are created by states, NGOs, companies, consumers, and other stakeholders. ‘Law’ might thus refer to a constant negotiation between public and private actors. Legal principles such as transparency, equal treatment, and the right to be heard would still be important.

Optimization of wood flour acetylation by factorial design and partial least squares regression

Acetylation was performed to reduce the polarity of wood and increase its compatibility with polymer matrices for the production of composites. These reactions were performed first as a function of acetic acid and anhydride concentration in a mixture catalyzed by sulfuric acid. A concentration of 50%/50% (v/v) of acetic acid and anhydride was found to produced the highest conversion rate between the functional groups. After these reactions, the kinetics were investigated by varying times and temperatures using a 3² factorial design, and showed time was the most relevant parameter in determining the conversion of hydroxyl into carbonyl groups.

A direct potentiometric titration study of the dissociation of humic acid with selectively blocked functional groups

A direct potentiometric titration method was applied to commercial and soil humic acids in order to determine their carboxyl and phenol group concentrations and apparent and intrinsic pK. In that context, acid-base properties of humic acids are interpreted by selective blocking of carboxylic and phenolic groups by esterification and acetylation. Differences in underivatized and derivatized HA's acid-base properties are ascribed to carboxyl and phenol groups influence on total humic acidity. Potentiometric data were treated with the modified Henderson-Hasselbalch equation. Infra red results, the acidic group contents and the average values of apparent and intrinsic pK for underivatized and derivatized HAs confirmed the selectivity of esterification derivatization method. After blocking of the functional groups, the values of acidic group contents decreased, while the value of apparent pK increased after derivatization. Phenol groups cannot be specifically identified by the acetylation method, due to low selectivity of the acetylation method.

Evaluation of group electronegativities and hardness (softness) of group 14 elements and containing functional groups through density functional theory and correlation with NMR spectra data

Quantum Chemical calculations for group 14 elements of Periodic Table (C, Si, Ge, Sn, Pb) and their functional groups have been carried out using Density Functional Theory (DFT) based reactivity descriptors such as group electronegativities, hardness and softness. DFT calculations were performed for a large series of tetracoordinated Sn compounds of the CH3SnRR'X type, where X is a halogen and R and R' are alkyl, halogenated alkyl, alkoxy, or alkyl thio groups. The results were interpreted in terms of calculated electronegativity and hardness of the SnRR'X groups, applying a methodology previously developed by Geerlings and coworkers (J. Phys. Chem. 1993, 97, 1826). These calculations allowed to see the regularities concerning the influence of the nature of organic groups RR' and inorganic group X on electronegativities and hardness of the SnRR'X groups; in this case, it was found a very good correlation between the electronegativity of the fragment and experimental 119Sn chemical shifts, a property that sensitively reflects the change in the valence electronic structure of molecules. This work was complemented with the study of some compounds of the EX and ER types, where E= C, Si, Ge, Sn and R= CH3, H, which was performed to study the influence that the central atom has on the electronegativity and hardness of molecules, or whether these properties are mainly affected for the type of ligand bound to the central atom. All these calculations were performed using the B3PW91 functional together with the 6-311++G** basis set level for H, C, Si, Ge, F, Cl and Br atoms and the 3-21G for Sn and I atoms.

Functional characterization of proteins required for mitotic progression and the spindle assembly checkpoint

During mitotic cell division, the genetic material packed into chromosomes is divided equally between two daughter cells. Before the separation of the two copies of a chromosome (sister chromatids), each chromosome has to be properly connected with microtubules of the mitotic spindle apparatus and aligned to the centre of the cell. The spindle assembly checkpoint (SAC) monitors connections between microtubules and chromosomes as well as tension applied across the centromere. Microtubules connect to a chromosome via kinetochores, which are proteinaceous organelles assembled onto the centromeric region of the sister chromatids. Improper kinetochore-microtubule attachments activate the SAC and block chromosome segregation until errors are corrected and all chromosomes are connected to the mitotic spindle in a bipolar manner. The purpose of this surveillance mechanism is to prevent loss or gain of chromosomes in daughter cells that according to current understanding contributes to cancer formation. Numerous proteins participate in the regulation of mitotic progression. In this thesis, the mitotic tasks of three kinetochore proteins, Shugoshin 1 (Sgo1), INCENP, and p38 MAP kinase (p38 MAPK), were investigated. Sgo1 is a protector of centromeric cohesion. It is also described in the tension-sensing mechanism of the SAC and in the regulation of kinetochore-microtubule connections. Our results revealed a central role for Sgo1 in a novel branch of kinetochore assembly. INCENP constitutes part of the chromosomal passenger complex (CPC). The other members of the core complex are the Aurora B kinase, Survivin and Borealin. CPC is an important regulatory element of cell division having several roles at various stages of mitosis. Our results indicated that INCENP and Aurora B are highly dynamic proteins at the mitotic centromeres and suggested a new role for CPC in regulation of chromosome movements and spindle structure during late mitosis. The p38 MAPK has been implicated in G1 and G2 checkpoints during the cell cycle. However, its role in mitotic progression and control of SAC signaling has been controversial. In this thesis, we discovered a novel function for p38γ MAPK in chromosome orientation and spindle structure as well as in promotion of viability of mitotic cells.

The role of selection in functional explanations

In this essay I will argue that natural selection is more important to functional explanations than what has been thought in some of the literature in philosophy of biology. I start by giving a brief overview of the two paradigms cases of functional explanations: etiological functions and causal-role functions. i then consider one particular attempt to conciliate both perspectives given by David Buller (1998). Buller's trial to conciliate both etiological functions and causal-role functions results in what he calls a weak etiological theory. I argue that Buller has not succeeded in his construal of the weak etiological theory: he underestimates the role that selective processes have in functional explanations and so his theory may not be classified as an etiologial theory. As an alternative, I consider the account of etiological functions given by Ruth Millikan (1984) and I argue that Millikan's theory is more comprehensive to assess contentious case in biology like exaptations. Finally, I conclude by analyzing where the adoption of Millikan's theory leave us. I argue, contrary to Millikan and others, that once we assume the importance of natural selection in functional explanations, there is no strong reason to resist a linguistic reform of the word function and hence that the attempts to conciliate both etiological functions and causal-role functions are misplaced.

Functional studies on bacterial nucleotide-regulated inorganic pyrophosphatases

CBS domains are ~60 amino acid tandemly repeated regulatory modules forming a widely distributed domain superfamily. Found in thousands of proteins from all kingdoms of life, CBS domains have adopted a variety of functions during evolution, one of which is regulation of enzyme activity through binding of adenylate-containing compounds in a hydrophobic cavity. Mutations in human CBS domain-containing proteins cause hereditary diseases. Inorganic pyrophosphatases (PPases) are ubiquitous enzymes, which pull pyrophosphate (PPi) producing reactions forward by hydrolyzing PPi into phosphate. Of the two nonhomologous soluble PPases, dimeric family II PPases, belonging to the DHH family of phosphoesterases, require a transition metal and magnesium for maximal activity. A quarter of the almost 500 family II PPases, found in bacteria and archaea, contain a 120-250 amino acid N-terminal insertion, comprised of two CBS domains separated in sequence by a DRTGG domain. These enzymes are thus named CBS-PPases. The function of the DRTGG domain in proteins is unknown. The aim of this PhD thesis was to elucidate the structural and functional differences of CBS-PPases in comparison to family II PPases lacking the regulatory insert. To this end, we expressed, purified and characterized the CBS-PPases from Clostridium perfringens (cpCBS-PPase) and Moorella thermoacetica (mtCBS-PPase), the latter lacking a DRTGG domain. Both enzymes are homodimers in solution and display maximal activity against PPi in the presence of Co2+ and Mg2+. Uniquely, the DRTGG domain was found to enable tripolyphosphate hydrolysis at rates similar to that of PPi. Additionally, we found that AMP and ADP inhibit, while ATP and AP4A activate CBSPPases, thus enabling regulation in response to changes in cellular energy status. We then observed substrate- and nucleotide-induced conformational transitions in mtCBS-PPase and found that the enzyme exists in two differentially active conformations, interconverted through substrate binding and resulting in a 2.5-fold enzyme activation. AMP binding was shown to produce an alternate conformation, which is reached through a different pathway than the substrate-induced conformation. We solved the structure of the regulatory insert from cpCBS-PPase in complex with AMP and AP4A and proposed that conformational changes in the loops connecting the catalytic and regulatory domains enable activity regulation. We examined the effects of mutations in the CBS domains of mtCBS-PPase on catalytic activity, as well as, nucleotide binding and inhibition.

Functional Study of Oncogenic Transcription Factor ERG and its Signaling in Prostate Cancer

TMPRSS2–ERG is the most frequent type of genomic rearrangement present in prostate tumors, in which the 5- prime region of the TMPRSS2 gene is fused to the ERG oncogene. TMPRSS2, containing androgen response elements (AREs), is regulated by androgens in the prostate. The truncated TMPRSS2-ERG fusion transcript is overexpressed in half of the prostate cancer patients. The formation of TMPRSS2-ERG transcript is an early event in prostate carcinogenesis and previous in vivo and in vitro studies have shown ectopic ERG expression to be associated with increased cell invasion. However, the molecular function of ERG and its role in cell signaling is poorly understood. In this study, genomic rearrangement of ERG with TMPRSS2 was studied by using comparative genomic hybridization (CGH) in prostate cancer samples. The biological processes associated with the ERG oncogene expression in prostate epithelial cells were studied, and the results were compared with findings observed in clinical prostate tumor samples. The gene expression data indicated that increased WNT signaling and loss of cell adhesion were a characteristic of TMPRSS2- ERG fusion positive prostate tumor samples. Up- regulation of WNT pathway genes were present in ERG positive prostate tumors, with frizzled receptor 4 (FZD4) presenting with the highest association with ERG overexpression, as verified by quantitative reverse transcription-PCR, immunostaining, and immunoblotting in TMPRSS2-ERG positive VCaP prostate cancer cells. Furthermore, ERG and FZD4 silencing increased cell adhesion by inducing active β1-integrin and E-cadherin expression in VCaP cells. Furthermore, we found a novel inhibitor, 4-(chloromethyl) benzoyl chloride which inhibited the WNT signaling and induced similar phenotypic effects as observed after ERG or FZD4 down regulation in VCaP cells. In conclusion, this work deepens our understanding on the complex oncogenic mechanisms of ERG in prostate cancer that may help in developing drugs against TMPRSS2-ERG positive tumors.

Conventional and novel cardiovascular risk factors in young Finns and their associations with structural and functional vascular changes of subclinical atherosclerosis. The Cardiovascular Risk in Young Finns Study

Background: Atherosclerosis begins in early life progressing from asymptomatic to symptomatic as we age. Although substantial progress has been made in identifying the determinants of atherosclerosis in middle to older age adults at increased cardiovascular risk, there is lack of data examining determinants and prediction of atherosclerosis in young adults. Aims: The current study was designed to investigate levels of cardiovascular risk factors in young adults, subclinical measures of atherosclerosis, and prediction of subclinical arterial changes with conventional risk factor measures and novel metabolic profiling of serum samples. Subjects and Methods: This thesis utilised data from the follow-ups performed in 2001 and 2007 in the Cardiovascular Risk in Young Finns study, a Finnish population-based prospective cohort study that examined 2,204 subjects who were aged 30-45 years in 2007. Subclinical atherosclerosis was studied using noninvasive ultrasound measurements of carotid intima-media thickness (IMT), carotid arterial distensibility (CDist) and brachial flow-mediated dilation (FMD). Measurements included conventional risk factors and metabolic profiling using highthroughput nuclear magnetic resonance (NMR) methods that provided data on 42 lipid markers and 16 circulating metabolites. Results: Trends in lipids were favourable between 2001 and 2007, whereas waist circumference, fasting glucose, and blood pressure levels increased. To study the stability of noninvasive ultrasound markers, 6-year tracking (the likelihood to maintain the original fractile over time) in 6 years was examined. IMT tracked more strongly than CDist and FMD. Cardiovascular risk scores (Framingham, SCORE, Finrisk, Reynolds and PROCAM) predicted subclinical atherosclerosis equally. Lipoprotein subclass testing did not improve the prediction of subclinical atherosclerosis over and above conventional risk factors. However, circulating metabolites improved risk stratification. Tyrosine and docosahexaenoic acid were found to be novel biomarkers of high IMT. Conclusions: Prediction of cardiovascular risk in young Finnish adults can be performed with any of the existing risk scores. The addition of metabonomics to risk stratification improves prediction of subclinical changes and enables more accurate targeting of prevention at an early stage.

Wood as a model material for medical biomaterials. In vivo and in vitro studies with bone and Betula pubescens Ehrh

Novel biomaterials are needed to fill the demand of tailored bone substitutes required by an ever‐expanding array of surgical procedures and techniques. Wood, a natural fiber composite, modified with heat treatment to alter its composition, may provide a novel approach to the further development of hierarchically structured biomaterials. The suitability of wood as a model biomaterial as well as the effects of heat treatment on the osteoconductivity of wood was studied by placing untreated and heat‐treated (at 220 C , 200 degrees and 140 degrees for 2 h) birch implants (size 4 x 7mm) into drill cavities in the distal femur of rabbits. The follow‐up period was 4, 8 and 20 weeks in all in vivo experiments. The flexural properties of wood as well as dimensional changes and hydroxyl apatite formation on the surface of wood (untreated, 140 degrees C and 200 degrees C heat‐treated wood) were tested using 3‐point bending and compression tests and immersion in simulated body fluid. The effect of premeasurement grinding and the effect of heat treatment on the surface roughness and contour of wood were tested with contact stylus and non‐contact profilometry. The effects of heat treatment of wood on its interactions with biological fluids was assessed using two different test media and real human blood in liquid penetration tests. The results of the in vivo experiments showed implanted wood to be well tolerated, with no implants rejected due to foreign body reactions. Heat treatment had significant effects on the biocompatibility of wood, allowing host bone to grow into tight contact with the implant, with occasional bone ingrowth into the channels of the wood implant. The results of the liquid immersion experiments showed hydroxyl apatite formation only in the most extensively heat‐treated wood specimens, which supported the results of the in vivo experiments. Parallel conclusions could be drawn based on the results of the liquid penetration test where human blood had the most favorable interaction with the most extensively heat‐treated wood of the compared materials (untreated, 140 degrees C and 200 degrees C heat‐treated wood). The increasing biocompatibility was inferred to result mainly from changes in the chemical composition of wood induced by the heat treatment, namely the altered arrangement and concentrations of functional chemical groups. However, the influence of microscopic changes in the cell walls, surface roughness and contour cannot be totally excluded. The heat treatment was hypothesized to produce a functional change in the liquid distribution within wood, which could have biological relevance. It was concluded that the highly evolved hierarchical anatomy of wood could yield information for the future development of bulk bone substitutes according to the ideology of bioinspiration. Furthermore, the results of the biomechanical tests established that heat treatment alters various biologically relevant mechanical properties of wood, thus expanding the possibilities of wood as a model material, which could include e.g. scaffold applications, bulk bone applications and serving as a tool for both mechanical testing and for further development of synthetic fiber reinforced composites.