Reconstitution of the destruction complex defines roles of AXIN polymers and APC in β-catenin capture, phosphorylation, and ubiquitylation.

The Wnt/β-catenin pathway is a highly conserved, frequently mutated developmental and cancer pathway. Its output is defined mainly by β-catenin's phosphorylation- and ubiquitylation-dependent proteasomal degradation, initiated by the multi-protein β-catenin destruction complex. The precise mechanisms underlying destruction complex function have remained unknown, largely because of the lack of suitable in vitro systems. Here we describe the in vitro reconstitution of an active human β-catenin destruction complex from purified components, recapitulating complex assembly, β-catenin modification, and degradation. We reveal that AXIN1 polymerization and APC promote β-catenin capture, phosphorylation, and ubiquitylation. APC facilitates β-catenin's flux through the complex by limiting ubiquitylation processivity and directly interacts with the SCFβ-TrCP E3 ligase complex in a β-TrCP-dependent manner. Oncogenic APC truncation variants, although part of the complex, are functionally impaired. Nonetheless, even the most severely truncated APC variant promotes β-catenin recruitment. These findings exemplify the power of biochemical reconstitution to interrogate the molecular mechanisms of Wnt/β-catenin signaling

Skjønnhetsidealet i reklame.

Hovedtemaet for denne bacheloroppgaven er skjønnhetsidealet i reklame, og om det har påvirkningskraft på selvbildet til unge kvinner. Målet med oppgaven er å se hvordan unge kvinner blir påvirket av skjønnhetsidealet reklame fremmer. Vi har innhentet data gjennom kvalitativ metode for å få best mulig kunnskap rundt problemstillingen: ”Hvordan påvirker reklame unge kvinners forståelse av egen kropp?” For å besvare problemstillingen har vi utført 12 dybdeintervju av unge kvinner i alderen 20-26 år som er bosatt i Oslo. Informantene kan fordeles utover en skala hvor den ene siden har stort fokus på trening, og den andre siden er de som ikke prioriter trening. Målet var ikke å generalisere utvalget vårt, men å skape en forståelse rundt fenomenet. I media har det vært mange debatter om at reklame er preget av seksualisering og retusjerte bilder, og at man er bekymret for forbrukerens selvbilde. Reklamebransjen retusjerer allerede vakre kvinner til å bli enda vakrere, og gjennom visuell kommunikasjon oppstår det et sett med uskrevne regler for hvordan en skal se ut, oppføre og kle seg i samfunnet. Det er ofte motebransjen som får kritikk for å fremme et helsefarlig skjønnhetsideal, men vi har valgt å se på hva som skjer når unge kvinner eksponeres for skjønnhetsidealet som reklamebransjen fremmer. I analysen har vi fokusert på emnene påvirkning, seksualisering, skjønnhetsidealet, selvbilde og sosialt nettverk. Vi har analysert intervjuene og koblet data opp mot relevant teori. Gjennom analysen av våre informanter konkluderer vi med at informantene også blir ubevisst påvirket av samfunnets forventninger til hva som er vakkert, hvordan man skal se ut og hva som er sosialt akseptert. Informantene var bevisst på at reklame ble retusjert og ikke var ekte, men allikevel sammenlignet de seg selv med bildene. Vi kom frem til at reklame har påvirkningskraft, men ikke alene, variabler som sosiale medier, venner, familie og kjendiser er med på å forme unge kvinner sitt selvbilde. Avslutningsvis kom vi frem til at den største konsekvensen med reklame er at selvbildet blir påvirket, og fører til at unge kvinner streber etter et skjønnhetsideal som er urealistisk

Hva gjør ledere i praksis? Samsvarer ledelsesteorier med en leders vanlige arbeidsdag?

Det finnes enormt mye teori rundt ledelse, og gjennom en lederutdanning har vi blitt kjent med mange av de klassiske. Disse fremstiller ofte ledelse som noe prosessuelt, reflektert og overordnet. Men stemmer det med hva ledelse egentlig er? Hva er det ledere driver med i hverdagen sin? Hva gjør ledere i praksis? Ved hjelp av kvalitativ metode gikk vi bredt ut for å få inn så mye informasjon som mulig. Vi dro ut for å observere 10 forskjellige ledere en vanlig dag på jobb. Vi så hva de brukte tiden sin til, hvordan de prioriterte og taklet alt som skulle løses og gjennomføres. Hovedfunnene våre går i all hovedsak ut på at ledere bruker tiden sin til mange administrative oppgaver, de skal håndtere mye informasjon og det skjer ad-hoc situasjoner kontinuerlig. Dette viser at mange av de ideelle teoriene som brukes i ledelsesundervisning bør suppleres med de kritiske teoriene som vi har funnet mye støtte i

N -butyldeoxynojirimycin reduces growth and ganglioside content of experimental mouse brain tumours

Abnormalities in glycosphingolipid (GSL) biosynthesis have been implicated in the oncogenesis and malignancy of brain tumours. GSLs comprise the gangliosides and the neutral GSLs and are major components of the cell surface glycocalyx. N -butyldeoxynojirimycin (N B-DNJ) is an imino sugar that inhibits the glucosyltransferase catalysing the first step in GSL biosynthesis. The influence of N B-DNJ was studied on the growth and ganglioside composition of two 20-methylcholanthrene-induced experimental mouse brain tumours, EPEN and CT-2A, which were grown in vitro and in vivo. N B-DNJ (200 μM) inhibited the proliferation of the EPEN and CT-2A cells by 50%, but did not reduce cell viability. The drug, administered in the diet (2400 mg kg−1) to adult syngeneic C57BL/6 mice, reduced the growth and ganglioside content of subcutaneous and intracerebral EPEN and CT-2A tumours by at least 50% compared to the untreated controls. N B-DNJ treatment also shifted the relative distribution of tumour gangliosides in accordance with the depletion of metabolic substrates. Side effects of N B-DNJ treatment were generally mild and included reductions in body and spleen weights and intestinal distension. We conclude that N B-DNJ may inhibit tumour growth through an effect on ganglioside biosynthesis and may be useful as a new chemotherapy for brain tumours. © 2001 Cancer Research Campaign http://www.bjcancer.co

Ar dreno pašalinimo laikas turi įtakos pirminio spontaninio pneumotorakso pirmojo epizodo gydymo išeitims?

Background / objectives. The main treatment option for the first episode of primary spontaneous pneumothorax is chest tube drainage, however, whether delayed chest tube removal might influence the recurrence is unclear.Methods. A prospective study, which included 50 patients, with an initial episode of primary spontaneous pneumothorax was performed. Patients were randomized into two groups according to the chest tube removal time: 1-day and 5-days after the air-leak has stopped. All patients were followed-up for at least six months. Both groups were compared according to the recurrence rate and possible complications.Results. There were 39 (78%) men and the median age was 27 (23–35) years. Successful management with a chest tube was achieved in 43 (86%) patients, others were operated on because of the continuous air-leak or relapse of the pneumothorax after the chest tube was removed. Significant difference was not found comparing groups by age, gender, side, tobacco smoking, alpha-1-antitrypsin level, rate of prolonged air-leak, necessity of surgery, and the mean follow-up time. There was a significant difference between groups in hospitalization time: 1-day group – 6 (4–12), 5-days group – 8 (7–10) days, p = 0.017. Five (20%) patients from 1-day group and 3 (12%) from 5-days group had a recurrence, however the difference was not significant (p = 0.702). There were no significant differences comparing groups by the recurrence time or complications.Conclusions. The recurrence rate of primary spontaneous pneumothorax was higher if the chest tube was removed earlier, however not significantly. More data and longer follow-up are necessary to confirm these findings.Įvadas / tikslas. Pirminis spontaninis pneumotoraksas yra didelė jaunų sveikų žmonių problema. Pleuros ertmės drenavimas – pagrindinis pirminio spontaninio pneumotorakso pirmojo epizodo gydymo būdas. Vis dėlto nėra žinoma, ar dreno buvimo pleuros ertmėje trukmė gali turėti įtakos recidyvų dažniui.Metodai. Atliktas perspektyvusis tyrimas, į kurį įtraukta 50 pacientų. Tiriamiesiems diagnozuotas pirminio spontaninio pneumotorakso pirmasis epizodas. Visi pacientai gydyti drenuojant pleuros ertmę. Pacientai suskirstyti į dvi grupes, atsižvelgiant į dreno pašalinimo laiką: praėjus vienai dienai ar praėjus penkioms dienoms, kai per dreną nustojo skirtis oras. Visi pacientai atokiu laikotarpiu (mažiausiai šešis mėnesius) stebėti dėl galimo recidyvo. Atlikta abiejų grupių recidyvų dažnio ir galimų komplikacijų lyginamoji analizė.Rezultatai. Vidutinis pacientų amžius – 27 (23–35) metai. 78 proc. tiriamųjų – vyrai. Drenavus pleuros ertmę, sėkmingai išgydyti 43 ligoniai (86 %). Kiti tiriamieji dėl besiskiriančio per dreną oro ar dėl rentgenogramoje matomo pakartotinio pneumotorakso, pašalinus dreną, buvo operuoti. Abiejų tiriamųjų grupių duomenys pagal amžių, lytį, pneumotorakso pasireiškimo krūtinės ląstoje pusę, rūkymą, alfa-1 antitripsino koncentraciją kraujyje, ilgesnį oro skyrimąsi per dreną ar operacijos poreikį statistiškai reikšmingai nesiskyrė. Statistiškai reikšmingai skyrėsi abiejų grupių hospitalizacijos trukmė: tiriamieji, kuriems, nustojus per dreną skirtis orui, drenas pašalintas praėjus vienai dienai, ligoninėje gulėjo vidutiniškai 6 (4–12) dienas, o tiriamieji, kuriems drenas pašalintas praėjus penkioms dienoms, – 8 (7–10) dienas (p = 0,017). Penkiems (20 %) pirmosios grupės ir trims (12 %) antrosios grupės pacientams pneumotoraksas recidyvavo (skirtumas statistiškai nereikšmingas (p = 0,702)). Statistiškai nereikšmingas skirtumas nustatytas ir tarp abiejų grupių recidyvo laiko bei komplikacijų.Išvados. Pirminio spontaninio pneumotorakso recidyvų dažnis kiek didesnis, kai drenas ištraukiamas anksčiau, tačiau lyginamųjų grupių skirtumas statistiškai nereikšmingas. Siekiant patvirtinti gautus rezultatus, reikia atlikti didesnės apimties tyrimą, būtina ilgiau stebėti tiriamuosius

Epidemiological and clinical profile of HIV-infected patients from Southwestern Goias State, Brazil

Knowledge about epidemiological distribution patterns of HIV infection in different geographic regions is relevant to understand the dynamics of the disease in Brazil. This study aims to characterize the epidemiological and clinical profile of HIV-infected patients from Southwestern Goias State, from 2005 to 2015. A standardized questionnaire was used to collect clinical-epidemiological, virological, and immunological data from the medical records of all HIV-infected patients (n=539) who were followed at the regional reference center of Jatai, Goias State, Brazil, from 2005 to 2015. We detected the prevalence of male patients and the heterosexual route of transmission, as well as an expressive number of young women infected with HIV. The HIV infection was more prevalent in reproductive ages (55.3%). Most patients presented clinical manifestations related to HIV infection at the time of diagnosis. Twenty-four patients presented coinfection with hepatitis C virus, syphilis, hepatitis B virus, leprosy or Chagas disease. Pneumonia caused by Pneumocystis jirovecii was the most common opportunistic infection, followed by neurotoxoplasmosis, tuberculosis, and neurocryptococcosis. Combined antiretroviral therapy improved CD4+ T-cell counts: the mean CD4+ T-cell counts after treatment was twice as high as those found at the first medical appointment; and highly active antiretroviral therapy promoted viral suppression in a significant number of patients. Considering the increasing distribution of HIV infection to the interior of Brazil, this descriptive study outlines the clinical-epidemiological characteristics of HIV infection in Southwestern Goias and contributes to develop local prevention strategies and public service plans

Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.

The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling