Surgical fusion of early onset severe scoliosis increases survival in Rett syndrome: A cohort study

Aim Scoliosis is a common co-morbidity in Rett syndrome and spinal fusion may be recommended if severe. We investigated the impact of spinal fusion on survival and risk of severe lower respiratory tract infection in Rett syndrome. Method Data were ascertained from hospital medical records, the Australian Rett Syndrome Database, a longitudinal and population-based registry, and from the Australian Institute of Health and Welfare National Death Index database. Cox regression and generalized estimating equation models were used to estimate the effects of spinal surgery on survival and severe respiratory infection respectively in 140 females who developed severe scoliosis (Cobb angle ≥45°) before adulthood. Results After adjusting for mutation type and age of scoliosis onset, the rate of death was lower in the surgery group (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.12–0.74; p=0.009) compared to those without surgery. Rate of death was particularly reduced for those with early onset scoliosis (HR 0.17, 95% CI 0.06–0.52; p=0.002). There was some evidence to suggest that spinal fusion was associated with a reduction in risk of severe respiratory infection among those with early onset scoliosis (risk ratio 0.41, 95% CI 0.16–1.03; p=0.06). Interpretation With appropriate cautions, spinal fusion confers an advantage to life expectancy in Rett syndrome.

Revisiting genetic structuring in spotted gums (genus Corymbia section Maculatae) focusing on C. maculata, an early diverged, insular lineage

Species delineation in the spotted gum complex was revisited focusing on Corymbia maculata. This study expands the range of C. maculata analysed with microsatellite markers to include populations from the north of the species range. It supported earlier findings that it is a cohesive genetic entity, well resolved from northern spotted gum taxa, Corymbia citriodora and Corymbia henryi; and inferences that its insularity is due to early lineage divergence and historical isolation. The northern extent of C. maculata sampled, as defined by chloroplast and nuclear genomes predominantly of C. maculata character, was the location of Kiwarrak, south of the Manning River near Taree in New South Wales. Trees from a recognised intergrade zone at the Yarratt locality, around 26 km north of Kiwarrak, also possessed a uniquely C. maculata chloroplast haplotype, but their nuclear genomes were predominantly of northern taxa ancestry. Range expansion of northern taxa leading to southerly gene movement into populations formerly C. maculata, would account for this apparent instance of chloroplast capture. Two subpopulations were identified in C. maculata, a northern population of which the Ourimbah locality was the most southerly studied, and a southern population of which Wingello was the most northerly locality studied. Diminished levels of northern taxa ancestry, i.e. C. citriodora or C. henryi, in individuals from the southern, relative to the northern subpopulation of C. maculata, suggested that secondary contact with northern taxa contributes to its substructure.

Franks family papers, 1711-1821, [1965-1968].

Contains business correspondence, accounts and documents relating to Jacob Franks of New York, his two sons, Moses and David, a nephew, Isaac, and a John Franks of Halifax, possibly a member of the family.

Contract with John Moore for building house on Mill Street

Digital image

Warrant to pay John Moore for building house on Mill Street

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A generic method of engagement to elicit regional coastal management options

Stakeholder engagement is important for successful management of natural resources, both to make effective decisions and to obtain support. However, in the context of coastal management, questions remain unanswered on how to effectively link decisions made at the catchment level with objectives for marine biodiversity and fisheries productivity. Moreover, there is much uncertainty on how to best elicit community input in a rigorous manner that supports management decisions. A decision support process is described that uses the adaptive management loop as its basis to elicit management objectives, priorities and management options using two case studies in the Great Barrier Reef, Australia. The approach described is then generalised for international interest. A hierarchical engagement model of local stakeholders, regional and senior managers is used. The result is a semi-quantitative generic elicitation framework that ultimately provides a prioritised list of management options in the context of clearly articulated management objectives that has widespread application for coastal communities worldwide. The case studies show that demand for local input and regional management is high, but local influences affect the relative success of both engagement processes and uptake by managers. Differences between case study outcomes highlight the importance of discussing objectives prior to suggesting management actions, and avoiding or minimising conflicts at the early stages of the process. Strong contributors to success are a) the provision of local information to the community group, and b) the early inclusion of senior managers and influencers in the group to ensure the intellectual and time investment is not compromised at the final stages of the process. The project has uncovered a conundrum in the significant gap between the way managers perceive their management actions and outcomes, and community's perception of the effectiveness (and wisdom) of these same management actions.

Child dietary and eating behaviour outcomes up to 3.5 years after an early feeding intervention: the NOURISH RCT

- Objective To evaluate dietary intake impact outcomes up to 3.5 years after the NOURISH early feeding intervention (concealed allocation, assessor masked RCT). - Methods 698 first-time mothers with healthy term infants were allocated to receive anticipatory guidance on protective feeding practices or usual care. Outcomes were assessed at 2, 3.7 and 5 years (3.5 years post-intervention). Dietary intake was assessed by 24-hour recall and Child Dietary Questionnaire. Mothers completed a food preference questionnaire and Children’s Eating Behaviour Questionnaire. Linear mixed models assessed group, time and time x group effects. - Results There were no group or time x group effects for fruit, vegetables, discretionary food and non-milk sweetened beverages intake. Intervention children showed a higher preference for fruits (74.6% vs 69.0% liked, P<.001), higher Child Dietary Questionnaire score for fruit and vegetables (15.3 vs 14.5, target>18, P=0.03), lower food responsiveness (2.3 vs 2.4, of maximum 5, P=.04) and higher satiety responsiveness (3.1 vs 3.0, of maximum 5, P=.04). - Conclusions Compared to usual care, an early feeding intervention providing anticipatory guidance regarding positive feeding practices led to small improvements in child dietary score, food preferences and eating behaviours up to 5 years of age, but not in dietary intake measured by 24-hour recall.

John Searlen teoria tietoisuudesta

Tutkielmassa esitellään ja arvioidaan John Searlen teoriaa tietoisuudesta. Tietoisuus (consciousness) on Searlen mukaan tärkein mielenfilosofinen käsite. Searle ei määrittele käsitettä tarkasti, vaan tyytyy esittämään sitä kuvaavia esimerkkejä ja analogioita. Tietoisuuden keskeisimmiksi ominaisuuksiksi Searlen teoriassa näyttävät muodostuvan intentionaalisuus (intentionality), subjektiivisuus (subjectivity) ja kausaalinen vaikutus käyttäytymiseen (mental causation). Näihin ominaisuuksiin liittyvät myös Searlen painavimmat tietoisuudesta esittämät argumentit. Argumenttien analysointi on tutkielman tärkein tavoite. Searlen yhteysperiaatteen (Connection Principle) mukaan intentionaalisia tiloja voi olla vain olennolla, jolla voi olla tietoisia intentionaalisia tiloja, ja jokainen alitajuinen intentionaalinen tila on ainakin potentiaalisesti tietoinen. Toisin sanoen intentionaalisuuden ja tietoisuuden välillä vallitsee välttämätön yhteys seuraavasti: on loogisesti välttämätöntä, että jokainen intentionaalinen tila voi ainakin periaattessa päästä tietoisuuteen.Tutkielmassa kuitenkin osoitetaan, että yhteysperiaateeseen on syytä suhtautua epäillen. Searlen yhteysperiaatteen puolesta esittämä argumentti näyttää nimittäin sisältävän dilemman. Jos erottelu intrinsiseen ja näennäiseen intentionaalisuuteen tulkitaan Searlen tavoin, syyllistytään sen olettamiseen, mikä pitäisi todistaa; jos taas erottelu tulkitaan toisin kuin Searle, argumentti ei tue yhteysperiaatetta. Searlen mukaan mentaaliset tilat ovat aina jonkun mentaalisia tiloja. Tästä väitteestä Searle pyrkii johtamaan toisen, paljon radikaalimman väitteen: mielen ilmiöt kuuluvat omaan ontologiseen kategoriaansa, subjektiivisten mentaalisten tilojen kategoriaan. Searlen käsitystä tukee Thomas Nagelin esittämä, hyvin samansisältöinen argumentti. Yksimielisyys ei kuitenkaan ole erehtymättömyyden tae, sillä Paul Churchlandin kritiikki näyttää pahasti horjuttavan Searlen subjektiivisuusargumentin uskottavuutta. Churchland väittää Searlen syyllistyvän intensionaaliseen virhepäätelmään. Yksittäisen henkilön episteemisen pääsyn rajoittuneisuudesta ei Churchlandin mukaan voida tehdä mitään ontologisia johtopäätöksiä, koska tiedetyksi tuleminen ei ole objektin aito ominaisuus. Vastaväite näyttää olevan kohtalokas Searlen subjektiivisuusargumentille. Subjektiivisuuden ongelma näyttää olevan perustava metafyysinen vedenjakaja, joka jakaa mielenfilosofiset teoriat toisaalta materialistisiin, toisaalta dualistisiin. Searle uskoo, että mieli-ruumis -ongelma (mind-body problem) on ratkaistavissa ilman, että tarvitsee valita kumpaakaan. Ratkaisu sisältyy kahteen Searlen näennäisesti yhteensopimattomaan teesiin. Ensimmäisen teesin mukaan mentaaliset tilat ovat todellisia ilmiöitä, eikä niitä voida redusoida mihinkään muuhun tai eliminoida määrittelemällä ne uudestaan. Toisen teesin mukaan aivojen operaatiot aiheuttavat mentaaliset tilat ja mentaaliset tilat ovat aivojen piirteitä. Teeseistä jälkimmäinen osoittautuu ongelmalliseksi syistä, jotka Jaegwon Kim on esittänyt. Jos mentaaliset tilat olisivat aivojen ominaisuuksia, ei mielen ja aivojen välinen suhde voisi olla kausaalinen, koska kausaatiossa (causation) on aina kyse kahden erillisen entiteetin tai tapahtuman välisestä relaatiosta, jossa suhteen osapuolien välillä on oltava ajallista etäisyyttä. Toiseksi Searlen vertaus tietoisuuden ja aivojen suhteesta kappaleen kiinteyden ja sen mikrorakenteen suhteeseen epäonnistuu, koska tietoisuus ja kiinteys kuuluvat Searlen teoriassa eri ontologisiin kategorioihin, eikä niitä siten voi ongelmattomasti rinnastaa. Searlen analogia kiinteyteen murtuu myös siksi, että kappaleen mikrorakenne ei yksinkertaisesti aiheuta sen kiinteyttä. Tietoisuus ei siis voi olla samanaikaisesti aivojen ominaisuus ja aivojen kausaalisen toiminnan seuraus. Tutkielmassa päädytään puolustamaan kantaa, että Searlen argumentit eivät ole vakuuttavia ja että Searle ei ole onnistunut eksplikoimaan teoriaa, joka välttäisi dualismiin ja materialismiin liittyvät tunnetut ongelmat. Kysymys mikä on mielen suhde ruumiiseen, jää siten avoimeksi. Avainsanat: intentionaalisuus, mentaalinen, mieli-ruumis -ongelma, Searle, subjektiivisuus, tietoisuus

Free energy calculations of the interactions of c-Jun-based synthetic peptides with the c-Fos protein

The c-Fos–c-Jun complex forms the activator protein 1 transcription factor, a therapeutic target in the treatment of cancer. Various synthetic peptides have been designed to try to selectively disrupt the interaction between c-Fos and c-Jun at its leucine zipper domain. To evaluate the binding affinity between these synthetic peptides and c-Fos, polarizable and nonpolarizable molecular dynamics (MD) simulations were conducted, and the resulting conformations were analyzed using the molecular mechanics generalized Born surface area (MM/GBSA) method to compute free energies of binding. In contrast to empirical and semiempirical approaches, the estimation of free energies of binding using a combination of MD simulations and the MM/GBSA approach takes into account dynamical properties such as conformational changes, as well as solvation effects and hydrophobic and hydrophilic interactions. The predicted binding affinities of the series of c-Jun-based peptides targeting the c-Fos peptide show good correlation with experimental melting temperatures. This provides the basis for the rational design of peptides based on internal, van der Waals, and electrostatic interactions.

Untitled (after Steven and John)

'Untitled (after Steven and John)' takes inspiration from Spielbergian tracking shots and Baldessarian collages to create ghostly apparitions that explore the affective power of the cinematic close up. By appropriating and obfuscating this common filmic convention, the work investigates the intersubjective potential of the moving image.

Farnesyltransferase Inhibitors Reduce Ras Activation and Ameliorate Acetaminophen-Induced Liver Injury in Mice

Hepatotoxicity due to overdose of the analgesic and antipyretic acetaminophen (A-PAIP) is a major cause of liver failure in adults. To better understand the contributions of different signaling pathways, the expression and role of Ras activation was evaluated after oral dosing of mice with APAP (400-500 mg/kg). Ras-guanosine triphosphate (GTP) is induced early and in an oxidative stress-dependent manner. The functional role of Ras activation was studied by a single intraperitoneal injection of the neutral sphingomyelinase and farnesyltransferase inhibitor (FTI) manumycin A (I mg/kg), which lowers induction of Ras-GTP and serum amounts of alanine aminotransferase (ALT). APAP dosing decreases hepatic glutathione amounts, which are not affected by manumycin A treatment. However, APAP-induced activation of c-Jun N-terminal kinase, which plays an important role, is reduced by manumycin A. Also, APAP-induced mitochondrial reactive oxygen species are reduced by manumycin A at a later time point during liver injury. Importantly, the induction of genes involved in the inflammatory response (including iNos, gp91phox, and Fasl) and serum amounts of proinflammatory cytokines interferon-gamma (IFN gamma) and tumor necrosis factor alpha, which increase greatly with APAP challenge, are suppressed with manumycin A. The FTI ctivity of manumycin A is most likely involved in reducing APAP-induced liver injury, because a specific neutral sphingomyelinase inhibitor, GW4869 (I mg/kg), did not show any hepatoprotective effect. Notably, a structurally distinct FTI, gliotoxin (I mg/kg), also inhibits Ras activation and reduces serum amounts of ALT and IFN-gamma after APAP dosing. Finally, histological analysis confirmed the hepatoprotective effect f manumycin A and gliotoxin during APAP-induced liver damage. Conclusion: This study identifies a key role for Ras activation and demonstrates the therapeutic efficacy of FTIs during APAP-induced liver injury.

Insight into the early stages of thermal unfolding of peanut agglutinin by molecular dynamics simulations

Peanut agglutinin is a homotetrameric nonglycosylated protein. The protein has a unique open quaternary structure. Molecular dynamics simulations have been employed follow the atomistic details of its unfolding at different temperatures. The early events of the deoligomerization of the protein have been elucidated in the present study. Simulation trajectories of the monomer as well as those of the tetramer have been compared and the tetramer is found to be substantially more stable than its monomeric counterpart. The tetramer shows retention of most of its.. secondary structure but considerable loss of the tertiary structure at high temperature. e generation of a This observation impies the molten globule-like intermediate in the later stages of deoligomerization. The quaternary structure of the protein has weakened to a large extent, but none of the subunits are separated. In addition, the importance of the metal-binding to the stability of the protein structure has also been investigated. Binding of the metal ions not only enhances the local stability of the metal-ion binding loop, but also imparts a global stability to the overall structure. The dynamics of different interfaces vary significantly as probed through interface clusters. The differences are substantially enhanced at higher temperatures. The dynamics and the stability of the interfaces have been captured mainly by cluster analysis, which has provided detailed information on the thermal deoligomerization of the protein.

Book Review: "The Interface: IBM and the Transformation of Corporate Design, 1945-1975", John Harwood, Minneapolis: University of Minnesota Press, 2011

Within the history of twentieth-century design, there are a number of well-known objects and stories that are invoked time and time again to capture a pivotal moment or summarize a much broader historical transition. For example, Marcel Breuer’s Model B3 chair is frequently used as a stand-in for the radical investigations of form and new industrial materials occurring at the Bauhaus in the mid-1920s. Similarly, Raymond Loewy’s streamlined pencil sharpener has become historical shorthand for the emergence of modern industrial design in the 1930s. And any discussion of the development of American postwar “organic design” seems incomplete without reference to Charles and Ray Eames’s molded plywood leg splint of 1942. Such objects and narratives are dear to historians of modern design. They are tangible, photogenic subjects that slot nicely into exhibitions, historical surveys, and coffee-table best sellers...