Crystallization and preliminary X-ray studies of the C-terminal domain of Mycobacterium tuberculosis LexA

The C-terminal domain of Mycobacterium tuberculosis LexA has been crystallized in two different forms. The form 1 and form 2 crystals belonged to space groups P3(1)21 and P3(1), respectively. Form 1 contains one domain in the asymmetric unit, while form 2 contains six crystallographically independent domains. The structures have been solved by molecular replacement.

Proton-bifurcated C-H center dot center dot center dot(O,O) hydrogen bonds in 2,3-dichloro-6-nitrobenzylaminium chloride

In the crystal structure of the title salt, C7H7Cl2N2O2+ center dot Cl-, the chloride anions participate in extensive hydrogen bonding with the aminium cations and indirectly link the molecules through multiple N+-H center dot center dot center dot Cl- salt bridges. There are two independent molecules in the asymmetric unit, related by a pseudo-inversion center. The direct intermolecular coupling is established by C-H center dot center dot center dot O, C-H center dot center dot center dot Cl and C-Cl center dot center dot center dot Cl- interactions. A rare three-center (donor bifurcated) C-H center dot center dot center dot (O,O) hydrogen bond is observed between the methylene and nitro groups, with a side-on intramolecular component of closed-ring type and a head-on intermolecular component.

Structure of 6,5'-anhydro-6-hydroxy-2',3' O-isopropylideneuridine

CI2HI4N206, Mr=282"3, orthorhombic,P21212 t, a = 10.412 (2), b = 14.936 (2), c =16.651(3),/k, V=2589.46A 3, Z--8, Din= 1.450, D x = 1.447 Mg m -3, 2(Cu Kct) = 1.5418/~, # =0.902mm -~, F(000)-- 1184.00, T= 293 K, R = 0.039, wR--0.038 for 2548 unique reflections with F > 3a(F). The two crystallographically independent molecules in the asymmetric unit have similar geome-tries with the ribose ring having an O(4')-exo, C(4')-endo pucker and the uracil base in the anti conformation.The geometry about the exocyclic C(4')-C(5') bond in both molecules is gauche-gauche. The dioxolane ring assumes twist conformations in both molecules.

Structure of N2-carbamoyl-L-asparagine

CsH9N304, M r= 175.1, orthorhombic,P212~2 ~, a = 7.486 (1), b = 9.919 (2), c =20.279 (2) A, V= 1505.8 A 3, z = 8, D x = 1.54, D m = 1.60 Mg m -3, ~,(Cu Ka) = 1.5418 A, g = 1. I I mm -~, F(000) = 736, T = 300 K, final R = 0.032 for 1345 observed reflections. The two independent molecules in the asymmetric unit are related by a pseudo twofold axis, with the asparagine side chains having different conformations [X 2 being -132.1 (3) and 139.6 (2)°]. The crystal structure is stabilized by extensive hydrogen bonding, with a specific interaction between the carboxyl group of one molecule and the carbamoyl group of another forming hydrogen-bonded chains.

mRNA-binding protein HuR in breast carcinogenesis

Breast cancer is the most common cancer among women. Although its prognosis has improved nowadays, methods to predict the progression of the disease or to treat it are not comprehensive. This thesis work was initiated to elucidate in breast carcinogenesis the role of HuR, a ubiquitously expressed mRNA-binding protein that regulates gene expression posttranscriptionally. HuR is predominantly nuclear, but it shuttles between the nucleus and the cytoplasm, and this nucleocytoplasmic translocation is important for its function as a RNA-stabilizing and translational regulator. HuR has been associated with diverse cellular processes, for example carcinogenesis. The specific aims of my thesis work were to study the prognostic value of HuR in breast cancer and to clarify the mechanisms by which HuR contributes to breast carcinogenesis. My ultimate goal is, by better understanding the role of HuR in breast carcinogenesis, to aid in the discovery of novel targets for cancer therapies. HuR expression and localization was studied in paraffin-embedded preinvasive (atypical ductal hyperplasia, ADH, and ductal carcinoma in situ, DCIS) specimens as well in sporadic and familial breast cancer specimens. Our results show that cytoplasmic HuR expression was already elevated in ADH and remained elevated in DCIS as well as in cancer specimens. Clinicopathological analysis showed that cytoplasmic HuR expression associated with the more aggressive form of the disease in DCIS, and in cancer specimens it proved an independent marker for poor prognosis. Importantly, cytoplasmic HuR expression was significantly associated with poor outcome in the subgroups of small (2 cm) and axillary lymph node-negative breast cancers. HuR proved to be the first mRNA stability protein the expression of which is associated in breast cancer with poor outcome. To explore the mechanisms of HuR in breast carcinogenesis, lentiviral constructs were developed to inhibit and to overexpress the HuR expression in a breast epithelial cell line (184B5Me). Our results suggest that HuR mediates breast carcinogenesis by participating in processes important in cell transformation, in programmed cell death, and in cell invasion. Global gene expression analysis shows that HuR regulates genes participating in diverse cellular processes, and affects several pathways important in cancer development. In addition, we identified two novel target transcripts (connective tissue growth factor, CTGF, and Ras oncogene family member 31, RAB31) for HuR. In conclusion, because cytoplasmic HuR expression in breast cancer can predict the outcome of the disease it could serve in clinics as a prognostic marker. HuR accumulates in the cytoplasm even at its non-invasive stage (ADH and DCIS) of the carcinogenic process and supports functions essential in cell alteration. These data suggest that HuR contributes to carcinogenesis of the breast epithelium.

Theoretical studies on alpha-helix--DNA interactions

The interaction energies between (Ala)10 and alpha-helix fragment and different nucleotide sequences in right-handed B-form have been optimized using semi-empirical potential energy functions. The energies are calculated for two different orientations of the alpha-helix, viz., when the alpha-helix axis taken in the N----C direction is (i) parallel and (ii) antiparallel to the 5'-3' ascending strand of DNA, proximal to it. When both the DNA molecule as well as the alpha-helix are treated as rigid molecules it is found that a polyalanine alpha-helix has slightly more favourable contacts when it is in the proximity of a four nucleotide sequence of 5'-(N-A-T-N)-3' type, where N is either a purine or a pyrimidine. However, when the two interacting molecules are allowed to undergo local structural variations then the interaction energy appears to be independent of the base sequence confirming the non-specific nature of these interactions.

The structure of ammonium oxalohydroxamate - a monopropellant

Abstract. NHn+.C2H3NzO4, Mr= 137.1, triclinic, Pi, a=3-952(1), b=6.772(1), c=9.993(1)A, a= 98.06 (1), fl= 89.96 (1), ~= 106.96 (1) °. V=253.06 A 3, z = 2, 2(Cu Ka) = 1.5418 A, g =15.29 cm -~, D m = 1.805, D x = 1.798 g cm -3, F(000)= 144, T= 293 K, R = 0.048 for 795 observed reflections. The unit cell contains two independent centrosymmetric molecules, one centred at (0,0,0) and the other at (0.5, 0.0, 0.5). The presence of experimentally determined~N-H groups and the -C=O bond lengths of 1.248 (4) and 1.247 (4)A indicate that the compound exists in the oxamic rather than the oximic form. Only one hydroxyl hydrogen is associated with each molecule. They are located at centres of inversion (0,0.5,0 and 0,0.5,0.5) and are shared between symmetry-related molecules via short symmetric H bonds with O...O=2.454(4), 2.457(4) and all O-H = 1.23 A

Polarization Caging in Diffusion-Controlled Electron Transfer Reactions in Solution

In some bimolecular diffusion-controlled electron transfer (ET) reactions such as ion recombination (IR), both solvent polarization relaxation and the mutual diffusion of the reacting ion pair may determine the rate and even the yield of the reaction. However, a full treatment with these two reaction coordinates is a challenging task and has been left mostly unsolved. In this work, we address this problem by developing a dynamic theory by combining the ideas from ET reaction literature and barrierless chemical reactions. Two-dimensional coupled Smoluchowski equations are employed to compute the time evolution of joint probability distribution for the reactant (P-(1)(X,R,t)) and the product (p((2))(X,R,t)), where X, as is usual in ET reactions, describes the solvent polarization coordinate and R is the distance between the reacting ion pair. The reaction is described by a reaction line (sink) which is a function of X and R obtained by imposing a condition of equal energy on the initial and final states of a reacting ion pair. The resulting two-dimensional coupled equations of motion have been solved numerically using an alternate direction implicit (ADI) scheme (Peaceman and Rachford, J. Soc. Ind. Appl. Math. 1955, 3, 28). The results reveal interesting interplay between polarization relaxation and translational dynamics. The following new results have been obtained. (i) For solvents with slow longitudinal polarization relaxation, the escape probability decreases drastically as the polarization relaxation time increases. We attribute this to caging by polarization of the surrounding solvent, As expected, for the solvents having fast polarization relaxation, the escape probability is independent of the polarization relaxation time. (ii) In the slow relaxation limit, there is a significant dependence of escape probability and average rate on the initial solvent polarization, again displaying the effects of polarization caging. Escape probability increases, and the average rate decreases on increasing the initial polarization. Again, in the fast polarization relaxation limit, there is no effect of initial polarization on the escape probability and the average rate of IR. (iii) For normal and barrierless regions the dependence of escape probability and the rate of IR on initial polarization is stronger than in the inverted region. (iv) Because of the involvement of dynamics along R coordinate, the asymmetrical parabolic (that is, non-Marcus) energy gap dependence of the rate is observed.

Determinants of Cognitive Impairment in Old Age and Their Genetic Architecture

Cognitive health is of central importance for independent and balanced old age, while memory disorders represent the leading cause of intensive and long-term care among the Finnish elderly. The aims of this study were to analyse the effect of height, body mass index, weight change, metabolic conditions and coffee drinking in midlife on cognitive performance in old age among a sample of 2606 Finnish twins aged 65 years or older who had participated in a telephone interview to assess their cognitive status. Since coffee drinking associates with several metabolic conditions and Finns are known to be the greatest consumers of coffee in the world, the heritability and stability of coffee drinking was analysed in the whole Older Finnish Twin Cohort (n=10716). In order to investigate the association between height and cognitive performance in a population with more supportive childhood living conditions, a total of 2161 Danish twins were included in this study. A greater height was found to clearly associate with better cognitive performance in Finnish subjects, but less so among the Danish sample, which may reflect the childhood environmental differences between these cohorts. In the Finnish subjects, there was greater variance in cognitive performance among shorter subjects, and environmental factors were found to play a greater role in their cognitive performance, whereas the cognitive performance of taller participants was mainly explained by genetic factors. Midlife metabolic variables that were found to be significantly associated with a poorer cognitive performance in old age included a higher body mass index and three metabolic conditions: cardiovascular disease, hypertension and, most significantly of all, diabetes. Moreover, both weight gain and loss, even to a lesser degree than suggested previously, were found to be associated with poorer cognition. Furthermore, evidence of a causal relationship between midlife cardiovascular disease and cognitive performance in old age was demonstrated among discordant twin pairs. Conversely, no effect of coffee drinking in midlife on cognitive performance in old age was observed, although coffee drinking was demonstrated to be stable in the study population. The heritability of coffee drinking was found to differ across sexes and age groups, being 51% in men and 52% in women in the whole study population. This study supports the contention that cognitive performance in old age reflects the effects of multiple genetic and environmental exposures, including their complex interactions during the life-span. The demonstrated associations and evidence of a causal pathway between potentially preventable exposures and poorer cognitive performance highlight the importance of preventive medicine.

”Waxaa i bartay hooyaday waawa u muhiim naaska caruurta.” Äitini opetti, että rintamaito on tärkeää lapselle. Osallistava tutkimus auktoritatiivisen tiedon omaksumisesta somalikulttuuritaustaisten naisten imetyskäytännöissä.

Suomessa asuvat somalitaustaiset maahanmuuttajaäidit luopuvat imetyksestä ja ruokkivat vauvojaan äidinmaidonkorvikkeella, vaikka somalikulttuurissa arvostetaan imetystä. Tuen ja tiedon puutetta on arveltu syyksi pulloruokinnan yleisyyteen. Tarkoituksenani on tutkia osallistavia menetelmiä käyttäen, minkälaisia imetykseen liittyviä tietojärjestelmiä somaliäidit pitävät auktoritatiivisina eli arvovaltaisina. Tarkastelen tiedon auktoritatiivisuutta etnografisten esimerkkien valossa hyödyntäen Brigitte Jordanin auktoritatiivisen tiedon käsitettä. Tutkin Jean Pierre Olivier de Sardanin teorian avulla, kuinka paikalliset populaarit tietojärjestelmät kohtaavat tieteellis-teknisen tiedon kehityksen kontekstissa. Tutkin myös, kuinka somaliäitien imetystietojärjestelmät kohtaavat suomalaisen terveydenhoitojärjestelmän edustaman imetystiedon. Osallistavien menetelmien tarkoituksena on saada heikkojen ja sorrettujen yhteisöjen ääni kuuluviin. Tutkimukseni tiedonantajina on seitsemäntoista somalimaahanmuuttajaäitiä ja yksi suomalainen äitiys- ja lastenneuvolan terveydenhoitaja. Käytän tiedonkeruumenetelminä puolistrukturoituja teemahaastatteluja, jonka lisäksi teen osallistuvaa havainnointia ja osallistavia menetelmiä kolmessa ryhmähaastattelutilanteessa. Käytän Rapi Rurad Appraisal (RRA) –menetelmiä, kuten Venn-diagrammia ja pisteytystä. Tutkimukseni tulos on, että somaliäitien imetykseen liittyvä tieto koostuu kolmesta tietojärjestelmästä, joita ovat sukuverkostoista tuleva perinteinen tietotaito, islaminuskon terveystieto sekä suomalaisen terveydenhoitojärjestelmän tieto. Näistä eri tietolähteistä tuleva imetystieto ei ole sisällöltään ristiriidassa. Imetykseen liittyvät vaikeudet ovat käytännön ongelmiin, kuten sukuverkoston hajoamiseen ja suomalaisen terveydenhoitojärjestelmän kanssa kommunikointiin liittyviä.

N-2-(4-Methyl-2-quinolyl)phenyl]acetamide: a P1 structure with Z=4

The title compound, C18H16N2O, crystallizes in the triclinic space group P1, with four independent molecules in the asymmetric unit wherein two molecules have an irregular -ac, -ac, +ap conformation (ap, antiperiplanar; ac, anticlinal), while the other molecules exhibit a different, +ac, +ac, +ap conformation. The planar (r.m.s. deviation = 0.006 A in each of the four molecules) quinoline ring systems of the four molecules are oriented at dihedral angles of 32.8 (2), 33.4 (2), 31.7 (2) and 32.3 (2)degrees with respect to the benzene rings. Intramolecular N-H...N interactions occur in all four independent molecules. The crystal packing is stabilized by intermolecular N-H...O and C-H...O hydrogen bonds, and are further consolidated by C-H...pi and pi-pi stacking interactions centroid-centroid distances = 3.728 (3), 3.722 (3), 3.758 (3) and 3.705 (3) A].

United We Stand - Divided We Fall : A Standard Model of Unit Cohesion

Research on unit cohesion has shown positive correlations between cohesion and valued outcomes such as strong performance, reduced stress, less indiscipline, and high re-enlistment intentions. However, the correlations have varied in strength and significance. The purpose of this study is to show that taking into consideration the multi-component nature of cohesion and relating the most applicable components to specific outcomes could resolve much of the inconsistency. Unit cohesion is understood as a process of social integration among members of a primary group with its leaders, and with the larger secondary groups of which they are a part. Correspondingly, included in the framework are four bonding components: horizontal (peer) and vertical (subordinate and leader) and organizational and institutional, respectively. The data were collected as part of a larger research project on cohesion, leadership, and personal adjustment to the military. In all, 1,534 conscripts responded to four questionnaires during their service in 2001-2002. In addition, sociometric questionnaires were given to 537 group members in 47 squads toward the end of their service. The results showed that platoons with strong primary-group cohesion differed from other platoons in terms of performance, training quality, secondary-group experiences, and attitudes toward refresher training. On the sociometric level it was found that soldiers who were chosen as friends by others were more likely to have higher expected performance, better performance ratings, more positive attitudes toward military service, higher levels of well-being during conscript service, and fewer exemptions from duty during it. On the group level, the selection of the respondents own group leader rather than naming a leader from outside (i.e., leader bonding) had a bearing not only on cohesion and performance, but also on the social, attitudinal, and behavioral criteria. Overall, the aim of the study was to contribute to the research on cohesion by introducing a model that takes into account the primary foci of bonding and their impact. The results imply that primary-group and secondary-group bonding processes are equally influential in explaining individual and group performance, whereas the secondary-group bonding components are far superior in explaining career intentions, personal growth, avoidance of duty, and attitudes toward refresher training and national defense. This should be considered in the planning and conducting of training. The main conclusion is that the different types of cohesion components have a unique, positive, significant, but varying impact on a wide range of criteria, confirming the need to match the components with the specific criteria.

Vanhustenhuolto + living lab = mahdollinen yhtälö? Tutkimus geronteknologisen järjestelmän tuotekehitysprosessista

Työ on laajaan dokumenttiaineistoon, haastatteluihin ja havaintoihin perustuva living lab - tyyppisen tuotekehitysprosessin yksityiskohtainen kuvaus. Hankehistoriallisessa tapaustutkimuksessa on käytetty historiantutkimuksen menetelmiä. Vanhustenkeskuksessa toteutetun living lab -hankkeen lopputuloksena syntyi vanhusten liikkeitä monitoroiva hoitotyön apuväline: turvalattia. Living lab -tyyppisessä tuotekehittämisessä on keskeistä teknologian kehittäminen tuotteen todellisessa käyttöympäristössä siten, että käyttäjät osallistuvat aktiivisesti kehitystyön kaikkiin vaiheisiin. Tutkimuksessa hankkeen etenemistä ja turvalattiateknologian rakentumista tarkastellaan toimijaverkostoteorian ja yhteisöllisen oppimisen käsitteen tarjoamista näkökulmista. Tutkimuksessa kiinnitetään erityisesti huomiota siihen, minkälaisia intressejä teknologian kehittämiseen osallistuvilla ryhmillä on ja minkälaisia konflikteja näiden intressien pohjalta syntyy. Lisäksi tarkastelun keskiössä on käyttäjien ja tuotekehittäjien välinen oppiminen, jonka mahdollistaminen ja edistäminen on living lab -kehittämisen päämäärä. Tutkimuksen keskeinen johtopäätös on, että käyttäjiltä saatu palaute on välttämätöntä käyttökelpoisen sosiaali- ja terveydenhuollon alan teknologian aikaansaamiseksi, ja turvalattian tapauksessa käyttäjäpalaute myös uudelleensuuntasi teknologisen järjestelmän innovaatioprosessia. Käyttäjien ja tuotekehittäjien yhteistyön myötä turvalattiaan kehitettiin joukko uusia toiminnallisuuksia ja käsitys tuotteen ydinominaisuuksista sekä hyötylupauksesta muuttuivat. Turvalattian tapaus osoittaa lisäksi yhteisöllisen oppimisen merkityksen innovaatioprosessissa sekä living lab -tyyppisen tuotekehittämisen potentiaalin näiden oppimisprosessien mahdollistajana ja kiihdyttäjänä. Tapaus myös valottaa sitä, kuinka monimutkainen toimintakenttä vanhustenhuolto on teknologian kehittämisen ja sen käyttöönoton näkökulmasta. Näyttäisi kuitenkin siltä, että living lab -metodologian avulla voidaan ylittää joitakin geronteknologian kehittämiseen ja myös käyttöönottoon liittyviä haasteita.

Drug epidemiology, interactions and pharmacogenetics : A post-mortem database study

Use of adverse drug combinations, abuse of medicinal drugs and substance abuse are considerable social problems that are difficult to study. Prescription database studies might fail to incorporate factors like use of over-the-counter drugs and patient compliance, and spontaneous reporting databases suffer from underreporting. Substance abuse and smoking studies might be impeded by poor participation activity and reliability. The Forensic Toxicology Unit at the University of Helsinki is the only laboratory in Finland that performs forensic toxicology related to cause-of-death investigations comprising the analysis of over 6000 medico-legal cases yearly. The analysis repertoire covers most commonly used drugs and drugs of abuse, and the ensuing database contains also background information and information extracted from the final death certificate. In this thesis, the data stored in this comprehensive post-mortem toxicology database was combined with additional metabolite and genotype analyses that were performed to complete the profile of selected cases. The incidence of drug combinations possessing serious adverse drug interactions was generally low (0.71%), but it was notable for the two individually studied drugs, a common anticoagulant warfarin (33%) and a new generation antidepressant venlafaxine (46%). Serotonin toxicity and adverse cardiovascular effects were the most prominent possible adverse outcomes. However, the specific role of the suspected adverse drug combinations was rarely recognized in the death certificates. The frequency of bleeds was observed to be elevated when paracetamol and warfarin were used concomitantly. Pharmacogenetic factors did not play a major role in fatalities related to venlafaxine, but the presence of interacting drugs was more common in cases showing high venlafaxine concentrations. Nicotine findings in deceased young adults were roughly three times more prevalent than the smoking frequency estimation of living population. Contrary to previous studies, no difference in the proportion of suicides was observed between nicotine users and non-nicotine users. However, findings of abused substances, including abused prescription drugs, were more common in the nicotine users group than in the non-nicotine users group. The results of the thesis are important for forensic and clinical medicine, as well as for public health. The possibility of drug interactions and pharmacogenetic issues should be taken into account in cause-of-death investigations, especially in unclear cases, medical malpractice suspicions and cases where toxicological findings are scarce. Post-mortem toxicological epidemiology is a new field of research that can help to reveal problems in drug use and prescription practises.

b-Turn conformations in crystal structures of model peptides containing a,a-di-n-propylglycine (Dpg) and a,a-di-n-butyl-glycine (Dbg).

The crystal state conformations of three peptides containing the a,a-dialkylated residues, a,adi n-propylglycine (Dpg) and a,@-di-n-butylglycine (Dbg), have been established by x-ray diffraction. Boc-Ala-Dpg-Ala-OMe ( I ) and Boc-Ala-Dbg-Ala-OMe (III) adopt distorted type II @-turn conformations with Ala ( I ) and Dpg/Dbg (2) as the corner residues. In both peptides the conformational angles at the Dxg residue (I: 4 = 66.23 J/ = 19.3'; III: 4 = 66S0, J. = 21 .la)deviate appreciablyfrom ideal values for the i + 2 residue in a type II @-turn. In both peptides the observed(N. 0) distances between the Boc CO andAla(3) NHgroups are far too long (I:3.44 k; III: 3.63 k) for an intramolecular 4 + 1 hydrogen bond. Boc-Ala-Dpg-Ala-NHMe (II)crystallizes with two independent molecules in the asymmetric unit. Both molecules IIA and IIB adopt consecutive @-turn (type III-III in IIA and type III-I in IIB) or incipient 3,,,-helical structures, stabilized by two intramolecular 4 --t I hydrogen bonds. In all four molecules the bond angle N-C"-C' ( T ) at the Dxg residues are 2 1109 The observation of conformational angles in the helical region of 4,J/ space at these residues is consistent with theoretical predictions