From neural stem cells to precursors : Molecular regulation of self-renewal and differentiation

Stem cells are responsible for tissue turnover throughout lifespan. Only highly controlled specific environment, the stem cell niche , can sustain undifferentiated stem cell-pool. The balance between maintenance and differentiation is crucial for individual s health: uncontrolled stem cell self-renewal or proliferation can lead to hyperplasia and mutations that further provoke malignant transformation of the cells. On the other hand, uninhibited differentiation may result in diminished stem cell population, which is unable to maintain tissue turnover. The mechanisms that control the switch from maintenance to differentiation in stem cells are not well known. The same mechanisms that direct the self-renewal and proliferation in normal stem cells are likely to be also involved in maintenance of cancer stem cell . Cancer stem cells exhibit stem cell like properties such as self-renewal- and differentiation capacity and they can also regenerate the tumor tissue. In this thesis, I have investigated the effect of classical oncogenes E6/E7 and c-Myc, tumor suppressors p53 and retinoblastoma (pRb) family, and vascular endothelial growth factor (VEGF) subfamily and glial cell line-derived neurothropic factor (GDNF) family ligands on behavior of embryonic neural stem cells (NSCs) and progenitors. The study includes also the characterization of cytoskeletal tumor suppressor neurofibromatosis 2 (NF2) protein merlin and ezrin-radixin-moesin (ERM) protein ezrin expression in neural progenitors cells and their progeny. This study reveals some potential mechanisms regarding to NSCs maintenance. In summary, the studied molecules are able to shift the balance either towards stem cell maintenance or differentiation; tumor suppressor p53 represses whereas E6/E7 oncogenes and c-Myc increase the proportion of self-renewing and proliferating NSCs or progenitors. The data suggests that active MEK-ERK signaling is critical for self-renewal of normal and oncogene expressing NSCs. In addition, the results indicate that expression of cytoskeletal tumor suppressor merlin and ERM protein ezrin in central nervous system (CNS) tissue and progenitors indicates their role in cell differentiation. Furthermore, the data suggests that VEGF-C a factor involved in lymphatic system development, angiogenesis, neovascularization and metastasis but also in maintenance of some neural populations in brain is a novel thropic factor for progenitors in early sympathetic nervous system (SNS). It seems that VEGF-C dose dependently through ERK-pathway supports the proliferation and survival of early sympathetic progenitor cells, and the effect is comparable to that of GDNF family ligands.

Clinical aspects of exhaled nitric oxide in adults : Associations with atopy, bronchial hyperresponsiveness, smoking and chronic obstruction

Measurement of fractional exhaled nitric oxide (FENO) has proven useful in assessment of patients with respiratory symptoms, especially in predicting steroid response. The objective of these studies was to clarify issues relevant for the clinical use of FENO. The influence of allergic sensitization per se on FENO in healthy asymptomatic subjects was studied, the association between airway inflammation and bronchial hyperresponsiveness (BHR) in steroid-naive subjects with symptoms suggesting asthma was examined, as well as the possible difference in this association between atopic and nonatopic subjects. Influence of smoking on FENO was compared between atopic and nonatopic steroid-naive asthmatics and healthy subjects. The short-term repeatability of FENO in COPD patients was examined in order to assess whether the degree of chronic obstruction influences the repeatability. For these purposes, we studied a random sample of 248 citizens of Helsinki, 227 army conscripts with current symptoms suggesting asthma, 19 COPD patients, and 39 healthy subjects. FENO measurement, spirometry and bronchodilatation test, structured interview. skin prick tests, and histamine and exercise challenges were performed. Among healthy subjects with no signs of airway diseases, median FENO was similar in skin prick test-positive and –negative subjects, and the upper normal limit of FENO was 30 ppb. In atopic and nonatopic subjects with symptoms suggesting asthma, FENO associated with severity of exercise- or histamine-induced BHR only in atopic patients. FENO in smokers with steroid-naive asthma was significantly higher than in healthy smokers and nonsmokers. Among atopic asthmatics, FENO was significantly lower in smokers than in nonsmokers, whereas no difference appeared among nonatopic asthmatics. The 24-h repeatability of FENO was equally good in COPD patients as in healthy subjects. These findings indicate that allergic sensitization per se does not influence FENO, supporting the view that elevated FENO indicates NO-producing airway inflammation, and that same reference range can be applied to both skin prick test-positive and -negative subjects. The significant correlation between FENO and degree of BHR only in atopic steroid-naive subjects with current asthmatic symptoms supports the view that pathogenesis of BHR in atopic asthma is strongly involved in NO-producing airway inflammation, whereas in development of BHR in nonatopic asthma other mechanisms may dominate. Attenuation of FENO only in atopic but not in nonatopic smokers with steroid-naive asthma may result from differences in mechanisms of FENO formation as well as in sensitivity of these mechanisms to smoking in atopic and nonatopic asthma. The results suggest, however, that in young adult smokers, FENO measurement may prove useful in assessment of airway inflammation. The short-term repeatability of FENO in COPD patients with moderate to very severe disease and in healthy subjects was equally good.

'Mutiny on the Bounty': The genetic history of Norfolk Island reveals extreme gender-biased admixture

Background The Pacific Oceania region was one of the last regions of the world to be settled via human migration. Here we outline a settlement of this region that has given rise to a uniquely admixed population. The current Norfolk Island population has arisen from a small number of founders with mixed Caucasian and Polynesian ancestry, descendants of a famous historical event. The ‘Mutiny on the Bounty’ has been told in history books, songs and the big screen, but recently this story can be portrayed through comprehensive molecular genetics. Written history details betrayal and murder leading to the founding of Pitcairn Island by European mutineers and the Polynesian women who left Tahiti with them. Investigation of detailed genealogical records supports historical accounts. Findings Using genetics, we show distinct maternal Polynesian mitochondrial lineages in the present day population, as well as a European centric Y-chromosome phylogeny. These results comprehensively characterise the unique gender-biased admixture of this genetic isolate and further support the historical records relating to Norfolk Island. Conclusions Our results significantly refine previous population genetic studies investigating Polynesian versus Caucasian diversity in the Norfolk Island population and add information that is beneficial to future disease and gene mapping studies.

A Search for Energy Minimized Sequences of Proteins

In this paper, we present numerical evidence that supports the notion of minimization in the sequence space of proteins for a target conformation. We use the conformations of the real proteins in the Protein Data Bank (PDB) and present computationally efficient methods to identify the sequences with minimum energy. We use edge-weighted connectivity graph for ranking the residue sites with reduced amino acid alphabet and then use continuous optimization to obtain the energy-minimizing sequences. Our methods enable the computation of a lower bound as well as a tight upper bound for the energy of a given conformation. We validate our results by using three different inter-residue energy matrices for five proteins from protein data bank (PDB), and by comparing our energy-minimizing sequences with 80 million diverse sequences that are generated based on different considerations in each case. When we submitted some of our chosen energy-minimizing sequences to Basic Local Alignment Search Tool (BLAST), we obtained some sequences from non-redundant protein sequence database that are similar to ours with an E-value of the order of 10(-7). In summary, we conclude that proteins show a trend towards minimizing energy in the sequence space but do not seem to adopt the global energy-minimizing sequence. The reason for this could be either that the existing energy matrices are not able to accurately represent the inter-residue interactions in the context of the protein environment or that Nature does not push the optimization in the sequence space, once it is able to perform the function.

The crystal and molecular structure of benzyloxycarbonyl-a-amino-isobutyryl-L-prolyl-methylamide. The observation of an X2-Pro3 Type III b-turn

The crystal and molecular structure of N-benzyloxycarbonyl-a-aminoisobutyryl-L-prolyl methylamide, the amino terminal dipeptide fragment of alamethicin, has been determined using direct methods. The compound crystallizes in the orthorhombic system with the space group P212-21. Cell dimensions are a = 7.705 A, b = 11.365 A, and c = 21.904 A. The structure has been refined using conventional procedures to a final R factor of 0.054. The molecular structure possesses a 4 - 1 intramolecular N-H--0 hydrogen bond formed between the CO group of the urethane moiety and the NH group of the methylamide function. The peptide backbone adopts the type 111 P-turn conformation, with 42 = -51.0°, +* = -39.7",&j = -65.0', $3 = -25.4'. An unusual feature is the occurrence of the proline residue at position 3 of the P-turn. The observed structure supports the view that Aib residues initiate the formation of type 111 @-turn conformations. The pyrrolidine ring is puckered in Cy-exo fashion.

Influence of tool rake angle on the quality of pure magnesium chip-consolidated product

Chips were produced by orthogonal Cutting of cast pure magnesium billet with three different tool rake angles viz., -15 degrees, -5 degrees and +15 degrees on a lathe. Chip consolidation by solid state recycling technique involved cold compaction followed by hot extrusion. The extruded products were characterized for microstructure and mechanical properties. Chip-consolidated products from -15 degrees rake angle tools showed 19% increase in tensile strength, 60% reduction ingrain size and 12% increase in hardness compared to +15 degrees rake chip-consolidated product indicating better chip bonding and grain refinement. Microstructure of the fracture specimen Supports the abovefinding. On the overall, the present work high lights the importance of tool take angle in determining the quality of the chip-consolidated products. (C) 2009 Elsevier B.V. All rights reserved.

Identification of loci for migraine with aura

Common migraine, i.e. migraine with (MA) or without aura (MO), is a chronic neurological disorder affecting about 10% of the Caucasian population. In MA, migraine headache is preceded by visual, sensoric and/or dysphasic reversible aura symptoms. Twin and family studies have suggested a multifactorial mode of inheritance for common migraine, and a stronger genetic component for MA than for MO. Since there is no biological or genetic marker to identify common migraine, aura symptoms provide a distinctive character to identify those suspected of suffering from migraine. The aim of this study was to identify MA susceptibility loci in well-phenotyped migraine samples with familial predisposition using different gene mapping methods. Genes coding for endothelin1 and its receptors EDNRA and ENDRB are potential candidate genes for cortical spreading depression (CSD), which is considered to be the underlying mechanism of migraine aura. The role of these genes in MA was studied in 850 Finnish migraine cases and 890 control individuals. Rare homozygous EDNRA SNPs showed nominal association with MA and with the age of onset trait (20 years). This result was also detected in the pooled analysis on 648 German MA cases and 651 control individuals when the test was adjusted for gender and sample origin. Evaluation of SNP genotyping reactions with two different DNA polymerase enzymes ensured that the genotype quality was high, and thus the discovered associations are considered reliable. The role of the 19p13 region was studied in a linkage analysis of 72 Finnish MA families. This region contains two migraine-associated genes: CACNA1A, which is associated with a predisposition to a rare Mendelian form of MA, familial hemiplegic migraine (FHM), and the insulin receptor gene (INSR) that is associated with common migraine. No evidence of linkage between the 19p13 and MA was detected. A novel visual aura locus was mapped to chromosome 9q21-q22 with significant evidence of linkage using a genome-wide linkage approach in 36 Finnish MA families. Five additional, potential loci were also detected. The 9q21-q22 region has previously been linked to occipitotemporal lobe epilepsy and MA, both of which involve prominent visual symptoms. Our result further supports a shared background for these episodic disorders.

Preparation of reticulated MAX-phase support with morphology-controllable nanostructured ceria coating for gas exhaust catalyst devices

Reticulated porous Ti3AlC2 ceramic, a member of the MAX-phase family (Mn+1AXn phases, where M is an early transition metal, A is an A-group element, and X is carbon and/or nitrogen), was prepared from the highly dispersed aqueous suspension by a replica template method. Through a cathodic electrogeneration method, nanocrystalline catalytic CeO2 coatings were deposited on the conductive porous Ti 3AlC2 supports. By adjusting the pH value and cathodic deposition current, coatings exhibiting nanocellar, nanosheets-like, or bubble-free morphologies can be obtained. This work expects to introduce a novel practically feasible material system and a catalytic coating preparation technique for gas exhaust catalyst devices.

Knowledge unlatched : A global library consortium model for funding Open Access scholarly books

Specialist scholarly books, including monographs, allow researchers to present their work, pose questions and to test and extend areas of theory through long-form writing. In spite of the fact that research communities all over the world value monographs and depend heavily on them as a requirement of tenure and promotion in many disciplines, sales of this kind of book are in free fall, with some estimates suggesting declines of as much as 90% over twenty years (Willinsky 2006). Cashstrapped monograph publishers have found themselves caught in a negative cycle of increasing prices and falling sales, with few resources left to support experimentation, business model innovation or engagement with digital technology and Open Access (OA). This chapter considers an important attempt to tackle failing markets for scholarly monographs, and to enable the wider adoption of OA licenses for book-length works: the 2012 – 2014 Knowledge Unlatched pilot. Knowledge Unlatched is a bold attempt to reconfigure the market for specialist scholarly books: moving it beyond the sale of ‘content’ towards a model that supports the services valued by scholarly and wider communities in the context of digital possibility. Its success has powerful implications for the way we understand copyright’s role in the creative industries, and the potential for established institutions and infrastructure to support the open and networked dynamics of a digital age.

A Single Mammalian Mitochondrial Translation Initiation Factor Functionally Replaces Two Bacterial Factors

The mechanism of translation in eubacteria and organelles is thought to be similar. In eubacteria, the three initiation factors IF1, IF2, and IF3 are vital. Although the homologs of IF2 and IF3 are found in mammalian mitochondria, an IF1 homolog has never been detected. Here, we show that bovine mitochondrial IF2 (IF2mt) complements E. coli containing a deletion of the IF2 gene (E. coli ΔinfB). We find that IF1 is no longer essential in an IF2mt-supported E. coli ΔinfB strain. Furthermore, biochemical and molecular modeling data show that a conserved insertion of 37 amino acids in the IF2mt substitutes for the function of IF1. Deletion of this insertion from IF2mt supports E. coli for the essential function of IF2. However, in this background, IF1 remains essential. These observations provide strong evidence that a single factor (IF2mt) in mammalian mitochondria performs the functions of two eubacterial factors, IF1 and IF2.

Predictors of violent reconvictions and mortality among impulsive alcoholic violent offenders: A prospective study

Acts of violence lays a great burden on humankind. The negative effects of violence could be relieved by accurate prediction of violent recidivism. However, prediction of violence has been considered an inexact science hampered by scare knowledge of its causes. The study at hand examines risk factors of violent reconvictions and mortality among 242 Finnish male violent offenders exhibiting severe alcoholism and severe externalizing personality disorders. The violent offenders were recruited during a court-ordered 2-month inpatient mental status examination between 1990—1998. Controls were 1210 individuals matched by sex-, age-, and place of birth. After a 9-year non-incarcerated follow-up criminal register and mortality data were obtained from national registers. Risk analyses were applied to estimate odds and relative risk for recidivism and mortality. Risk variables that were included in the analyses were antisocial personality disorder (ASPD), borderline personality disorder (BPD), a comorbidity of ASPD and BPD, childhood adversities, alcohol consumption, age, and monoamine oxidase A (MAOA) genotype. In addition to risk analyses, temperament dimensions (Tridimensional Personality Questionnaire [TPQ]) were assessed. The prevalence of recidivistic acts of violence (32%) and mortality (16%) was high among the offenders. Severe personality disorders and childhood adversities increased the risk for recidivism and mortality both among offenders (OR 2.0–10.4) and in comparison between offenders and controls (RR 4.3–53.0). Offenders having BPD and a history of childhood maltreatment emerged as a group with a particularly poor prognosis. MAOA altered the effects of alcohol consumption and ageing. Alcohol consumption (+2.3%) and age (–7.3%) showed significant effects on the risk for violent reconvictions among the high activity MAOA (MAOA-H) offenders, but not among the low activity MAOA (MAOA-L) offenders. The offenders featured temperament dimensions of high novelty seeking, high harm avoidance, and low reward dependence matching Cloninger’s definition of explosive personality. The fact that the risk for recidivistic acts of violence and mortality accumulated into clearly defined subgroups supports future efforts to provide for evidence based violence prevention and risk assessments among violent offenders.

Inter-helical Interactions in Membrane Proteins: Analysis Based on the Local Backbone Geometry and the Side Chain Interactions

The availability of a significant number of the Structures of helical membrane proteins has prompted us to investigate the mode of helix-helix packing. In the present study, we have considered a dataset of alpha-helical membrane proteins representing Structures solved from all the known superfamilies. We have described the geometry of all the helical residues in terms of local coordinate axis at the backbone level. Significant inter-helical interactions have been considered as contacts by weighing the number of atom-atom contacts, including all the side-chain atoms. Such a definition of local axis and the contact criterion has allowed us to investigate the inter-helical interaction in a systematic and quantitative manner. We show that a single parameter (designated as alpha), which is derived from the parameters representing the Mutual orientation of local axes, is able to accurately Capture the details of helix-helix interaction. The analysis has been carried Out by dividing the dataset into parallel, anti-parallel, and perpendicular orientation of helices. The study indicates that a specific range of alpha value is preferred for interactions among the anti-parallel helices. Such a preference is also seen among interacting residues of parallel helices, however to a lesser extent. No such preference is seen in the case of perpendicular helices, the contacts that arise mainly due to the interaction Of Surface helices with the end of the trans-membrane helices. The Study Supports the prevailing view that the anti-parallel helices are well packed. However, the interactions between helices of parallel orientation are non-trivial. The packing in alpha-helical membrane proteins, which is systematically and rigorously investigated in this study, may prove to be useful in modeling of helical membrane proteins.

The Cooperative Research Centre for Living with Autism (Autism CRC) conceptual model to promote mental health for adolescents with ASD

Despite an increased risk of mental health problems in adolescents with Autism Spectrum Disorder (ASD), there is limited research on effective prevention approaches for this population. Funded by the Cooperative Research Centre for Living with Autism, a theoretically and empirically supported school-based preventative model has been developed to alter the negative trajectory and promote wellbeing and positive mental health in adolescents with ASD. This conceptual paper provides the rationale, theoretical, empirical and methodological framework of a multilayered intervention targeting the school, parents, and adolescents on the spectrum. Two important interrelated protective factors have been identified in community adolescent samples, namely the sense of belonging (connectedness) to school, and the capacity for self and affect regulation in the face of stress (i.e., resilience). We describe how a confluence of theories from social psychology, developmental psychology and family systems theory, along with empirical evidence (including emerging neurobiological evidence) supports the interrelationships between these protective factors and many indices of wellbeing. However, the characteristics of ASD (including social and communication difficulties, and frequently difficulties with changes and transitions, and diminished optimism and self-esteem) impair access to these vital protective factors. The paper describes how evidenced-based interventions at the school level for promoting inclusive schools (using the Index for Inclusion), and interventions for adolescents and parents to promote resilience and belonging (using the Resourceful Adolescent Program (RAP)), are adapted and integrated for adolescents with ASD. This multisite proof of concept study will confirm whether this multilevel school-based intervention is promising, feasible and sustainable.

Possible high-temperature superconducting state with a d plus id pairing symmetry in doped graphene

Motivated by a suggestion in our earlier work [G. Baskaran, Phys. Rev. B 65, 212505 (2002)], we study electron correlation driven superconductivity in doped graphene where on-site correlations are believed to be of intermediate strength. Using an extensive variational Monte Carlo study of the repulsive Hubbard model and a correlated ground state wave function, we show that doped graphene supports a superconducting ground state with a d+id pairing symmetry. We estimate superconductivity reaching room temperatures at an optimal doping of about 15%-20%. Our work suggests that correlations can stabilize superconductivity even in systems with intermediate coupling.

Brain imaging of chronic pain

Acute pain has substantial survival value because of its protective function in the everyday environment. Instead, chronic pain lacks survival and adaptive function, causes great amount of individual suffering, and consumes the resources of the society due to the treatment costs and loss of production. The treatment of chronic pain has remained challenging because of inadequate understanding of mechanisms working at different levels of the nervous system in the development, modulation, and maintenance of chronic pain. Especially in unclear chronic pain conditions the treatment may be suboptimal because it can not be targeted to the underlying mechanisms. Noninvasive neuroimaging techniques have greatly contributed to our understanding of brain activity associated with pain in healthy individuals. Many previous studies, focusing on brain activations to acute experimental pain in healthy individuals, have consistently demonstrated a widely-distributed network of brain regions that participate in the processing of acute pain. The aim of the present thesis was to employ non-invasive brain imaging to better understand the brain mechanisms in patients suffering from chronic pain. In Study I, we used magnetoencephalography (MEG) to measure cortical responses to painful laser stimulation in healthy individuals for optimization of the stimulus parameters for patient studies. In Studies II and III, we monitored with MEG the cortical processing of touch and acute pain in patients with complex regional pain syndrome (CRPS). We found persisting plastic changes in the hand representation area of the primary somatosensory (SI) cortex, suggesting that chronic pain causes cortical reorganization. Responses in the posterior parietal cortex to both tactile and painful laser stimulation were attenuated, which could be associated with neglect-like symptoms of the patients. The primary motor cortex reactivity to acute pain was reduced in patients who had stronger spontaneous pain and weaker grip strength in the painful hand. The tight coupling between spontaneous pain and motor dysfunction supports the idea that motor rehabilitation is important in CRPS. In Studies IV and V we used MEG and functional magnetic resonance imaging (fMRI) to investigate the central processing of touch and acute pain in patients who suffered from recurrent herpes simplex virus infections and from chronic widespread pain in one side of the body. With MEG, we found plastic changes in the SI cortex, suggesting that many different types of chronic pain may be associated with similar cortical reorganization. With fMRI, we found functional and morphological changes in the central pain circuitry, as an indication of central contribution for the pain. These results show that chronic pain is associated with morphological and functional changes in the brain, and that such changes can be measured with functional imaging.