Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae

Publisher Copyright: © 2022 The AuthorsNuclear factor κ light-chain enhancer of activated B cells (NF-κB) family of evolutionarily conserved transcription factors are involved in key cellular signaling pathways. Previously, hypogammaglobulinemia and common variable immunodeficiency (CVID)-like phenotypes have been associated with NFKB1 variants and loss-of-function NFKB1 variants have been reported as the most common monogenic cause for CVID among Europeans. Here, we describe a Finnish cohort of NFKB1 carriers consisting of 31 living subjects in six different families carrying five distinct heterozygous variants. In contrast to previous reports, the clinical penetrance was not complete even with advancing age and the prevalence of CVID/hypogammaglobulinemia was significantly lower, whereas (auto)inflammatory manifestations were more common (42% of the total cohort). At current stage of knowledge, routine genetic screening of asymptomatic individuals is not recommended, but counseling of potential adult carriers seems necessary.Peer reviewe

A Secreted BMP Antagonist, Cer1, Fine Tunes the Spatial Organization of the Ureteric Bud Tree during Mouse Kidney Development

The epithelial ureteric bud is critical for mammalian kidney development as it generates the ureter and the collecting duct system that induces nephrogenesis in dicrete locations in the kidney mesenchyme during its emergence. We show that a secreted Bmp antagonist Cerberus homologue (Cer1) fine tunes the organization of the ureteric tree during organogenesis in the mouse embryo. Both enhanced ureteric expression of Cer1 and Cer1 knock out enlarge kidney size, and these changes are associated with an altered three-dimensional structure of the ureteric tree as revealed by optical projection tomography. Enhanced Cer1 expression changes the ureteric bud branching programme so that more trifid and lateral branches rather than bifid ones develop, as seen in time-lapse organ culture. These changes may be the reasons for the modified spatial arrangement of the ureteric tree in the kidneys of Cer1+ embryos. Cer1 gain of function is associated with moderately elevated expression of Gdnf and Wnt11, which is also induced in the case of Cer1 deficiency, where Bmp4 expression is reduced, indicating the dependence of Bmp expression on Cer1. Cer1 binds at least Bmp2/4 and antagonizes Bmp signalling in cell culture. In line with this, supplementation of Bmp4 restored the ureteric bud tip number, which was reduced by Cer1+ to bring it closer to the normal, consistent with models suggesting that Bmp signalling inhibits ureteric bud development. Genetic reduction of Wnt11 inhibited the Cer1-stimulated kidney development, but Cer1 did not influence Wnt11 signalling in cell culture, although it did inhibit the Wnt3a-induced canonical Top Flash reporter to some extent. We conclude that Cer1 fine tunes the spatial organization of the ureteric tree by coordinating the activities of the growth-promoting ureteric bud signals Gndf and Wnt11 via Bmp-mediated antagonism and to some degree via the canonical Wnt signalling involved in branching

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Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells

Peer reviewe

Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells

Peer reviewe

A Cryptic Frizzled Module in Cell Surface Collagen 18 Inhibits Wnt/β−Catenin Signaling

Collagens contain cryptic polypeptide modules that regulate major cell functions, such as cell proliferation or death. Collagen XVIII (C18) exists as three amino terminal end variants with specific amino terminal polypeptide modules. We investigated the function of the variant 3 of C18 (V3C18) containing a frizzled module (FZC18), which carries structural identity with the extracellular cysteine-rich domain of the frizzled receptors. We show that V3C18 is a cell surface heparan sulfate proteoglycan, its topology being mediated by the FZC18 module. V3C18 mRNA was expressed at low levels in 21 normal adult human tissues. Its expression was up-regulated in fibrogenesis and in small well-differentiated liver tumors, but decreased in advanced human liver cancers. Low FZC18 immunostaining in liver cancer nodules correlated with markers of high Wnt/β−catenin activity. V3C18 (Mr = 170 kD) was proteolytically processed into a cell surface FZC18-containing 50 kD glycoprotein precursor that bound Wnt3a in vitro through FZC18 and suppressed Wnt3a-induced stabilization of β−catenin. Ectopic expression of either FZC18 (35 kD) or its 50 kD precursor inhibited Wnt/β−catenin signaling in colorectal and liver cancer cell lines, thus downregulating major cell cycle checkpoint gatekeepers cyclin D1 and c-myc and reducing tumor cell growth. By contrast, full-length V3C18 was unable to inhibit Wnt signaling. In summary, we identified a cell-surface signaling pathway whereby FZC18 inhibits Wnt/β−catenin signaling. The signal, encrypted within cell-surface C18, is released by enzymatic processing as an active frizzled cysteine-rich domain (CRD) that reduces cancer cell growth. Thus, extracellular matrix controls Wnt signaling through a collagen-embedded CRD behaving as a cell-surface sensor of proteolysis, conveying feedback cues to control cancer cell fate

Opiskelijat laatutyössä Lahden ammattikorkeakoulussa

Tämän opinnäytetyön tavoitteena oli selvittää Lahden ammattikorkeakoulun opiskelijoiden osallistumista laatutyöhön ja löytää Korkeakoulujen arviointineuvoston auditointiraportteja tutkimalla hyviä käytänteitä opiskelijoiden aktivoimiseksi osallistumaan ja kehittämään korkeakoulun laatukulttuuria. Laatukulttuurin kehittämistä tarkastellaan opiskelijan osallistumismahdollisuuksien parantamisen ja kehittämisen kannalta. Lisäksi opinnäytetyössä pohdittiin hyväksi koetun palvelun laadun kriteerien toteutumista ja soveltuvuutta korkeakouluun. Teoreettinen viitekehys koostuu palvelun laadusta ja sen tunnuspiirteistä korkeakoulutuksessa ja millaisista asioista muodostuu korkeakouluorganisaation palvelun laatu. Opinnäytetyö on tehty toimeksiantona Lahden ammattikorkeakoululle. Opinnäytetyön empiirinen osuus toteutettiin tutkimalla yhteensä 22 Korkeakoulujen arviointineuvoston auditointiraporttia vuosilta 2007–2014. Näistä löydettiin 437 suositusta tai mainintaa hyvistä käytänteistä. Löydetyt suositukset ja maininnat luetteloitiin seuraavien mainintojen alle:opiskelijoiden osallistaminen, opiskelijapalaute, kyselyt ja dokumentaatio,vastapalaute, opiskelijapalautejärjestelmä/laatujärjestelmä ja opiskelijoiden laatukäsikirja, esitteet ja muu materiaali. Syntynyttä aineistoa hyödyntäen tehtiin kehittämisehdotukset opiskelijoiden laatutyöhön osallistamisen ja sitouttamisen lisäämiseksi ja siten Lahden ammattikorkeakoulun laatukulttuurin vahvistamiseksi. Kehittämisehdotukset Lahden ammattikorkeakoululle kirjattiin kehittämisen työkirjaan. Keskeisiksi kehittämiskohteiksi nostettiin opiskelijoiden osallistamisen lisääminen, opiskelijapalaute, palautteen palaute/vastapalaute, opiskelijapalautejärjestelmä, opiskelijoiden laatukäsikirja ja ura- ja rekrytointipalvelu ja alumnitoiminta.The purpose of this thesis was to find out the level of student involvement in the quality work practiced at Lahti University of Applied Sciences. In addition, by analyzing the audition reports of the Finnish Higher Education Evaluation Council (FINHEEC), the aim was to find good practices in activating students to give feedback and to participate in a higher education institution’s (HEI) quality culture. The development of quality culture is examined from the perspective of improving and developing students’ opportunities to participate. In addition, proven good service criteria and their realization in Higher Education Institutions (HEIs) is discussed in the thesis. The theoretical framework of the thesis consists of a discussion on the quality of service and its characteristics in Higher Education Institutions. This part of the thesis also discusses the key factors creating quality at Higher Education Institutions. This study was made as an assignment to Lahti University of Applied Sciences. The empirical section of the study was implemented by benchmarking 22 FINHEEC’s audition reports between 2007 and 2014 from which 437 good practices and recommendations were found. By applying the material, development propositions were made to increase student involvement in quality work, thus strengthening the quality culture at Lahti University of Applied Sciences. The good practices and recommendations were categorized as follows: student involvement, student feedback, questionnaires and documentation, feedback on feedback, the student feedback system, the quality system, the student quality manual, and brochures and other material. The development propositions were entered in the University’s development workbook. The essential propositions to Lahti University of Applied Sciences included the following: increasing student involvement, student feedback, feedback on feedback, a student feedback system, a student quality manual, career and recruitment services and alumni activities

Kohderyhmän kokema motivoituminen ja voimaantuminen ITU-projektissa

Tässä opinnäytetyössä oli tarkoituksena tutkia ESR:n (Euroopan Sosiaalirahasto) ja Lahden kaupungin rahoittaman sekä Lahden seudun työttömät ry:n hallinnoiman ITU-projektin kohderyhmän kokemaa voimaantumista ja motivaation mahdollista paranemista ryhmän osallistuessa projektin toimintaan. Teoreettisessa osuudessa tarkasteltiin motivaatiota ja voimaantumista eri teorioiden ja tutkimusten valossa, jotta saataisiin muodostettua kuva siitä mitä niillä tämänhetkisen tutkimuksen valossa ymmärretään ja kuinka ihmisen motivoitumista ja/tai voimaantumista yleensäkään voidaan tukea tai lisätä. Lisäksi tarkasteltiin kokemusta ja sen tutkimista. Empiirisen osuuden aineisto kerättiin kohderyhmän jäsenten kirjoittamista kirjoitelmista, joissa heitä pyydettiin kertomaan omin sanoin kokemuksiaan siitä, mitä heille on tapahtunut projektin aikana, mitä uusia taitoja he ovat oppineet, mikä on heidän mielestään ollut projektin parasta antia ja miten projekti voisi parantaa vielä toimintaansa. Lisäksi heitä pyydettiin kuvailemaan onnistumisen kokemuksiaan ITU-projektiin osallistumisen ja tukityöllistymisen aikana ja jos mahdollista, kuvailemaan miltä onnistuminen tuntui. Kirjoitelmien lauselmat kategorioitiin motivoitumisen sysäyksiksi, voimaantumisen kokemuksiksi ja kritisoiviksi ennakkoasenteiksi. Kirjoitelmien lausumat analysoitiin sisällönanalyysillä. Motivoitumista ilmaistiin kiitoksen ja rohkaisun saamisella. Projektin kautta saadun tiedon, tuen ja kannustuksen merkitys sekä vertaistuki nähtiin myös tärkeinä. Voimaantumisen kategoriassa esiin nousivat ATK-koulutus, terveystarkastus ja kuntotestaus. Tärkeinä koettiin myös oman sosiaalisuuden ja itseluottamuksen voimistuminen, sekä rohkaistuminen ja vastuunotto omista valinnoista ja elämästä. Kritiikkiä ITU-projekti sai siitä, että toiminnan sovittaminen yhteen työnteon kanssa koettiin hankalaksi. Erityisesti luentomuotoiset päivät koettiin pitkästyttäviksi ja koettiin, että samoja asioita toistettiin liikaa.The experienced motivation and empowerment of the members of the ITU-project. ABSTRACT The purpose of this study is to examine the experienced motivation and empowerment of the target group in ITU project, which is financed by ESF (The European Social Fund) and the city of Lahti and administered by Lahden seudun työttömät registered association. In the theoretical part of this study, motivation and empowerment are analyzed in view of different theories and studies about the subject. That helped to understand the current research atmosphere of motivation and empowerment. It was also interesting to study whether it is possible to have an effect on an individual's motivation and/or empowerment and if so, how. In addition, the experience and analysis of the experience were examined. The empirical data was collected with essays written by the target group. In the essays people were asked to tell about their experiences of the project: what had happened to them during the project, what new skills they felt they had learned, what were the best experiences in the project and what suggestions they had for improving the project. In addition, they were asked to describe experiences of success while participating in the project and during their subsidized employment. The essays were organized into three categories: an impulse for motivation, an experience of empowerment and a bias due to critical attitude. The essays were examined by analysis of the content. Motivation was expressed as getting acknowledgement and encouragement. Also the knowledge, support of the peer group and encouragement of the ITU-project were important. An ADP education, physical examination and fitness condition testing were quoted as empowering experiences. The ITU-project was criticized for difficulty to fit together the activities of the project and work. Lectures were experienced to be boring and repetitive