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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Linguistics in Potsdam
(1994)
Pancreatic secretory zymogen-granule membrane glycoprotein 2 (GP2) has been identified as a major autoantigenic target in Crohn’s disease patients. It was reported recently that a long (GP2a) and a short (GP2b) isoform of GP2 exist and that in the outcome of inflammatory bowel diseases (IBD) GP2-specific autoantibodies probably appear as new serological markers for diagnosis and therapeutic monitoring. To investigate this further and in order to establish diagnostic tools for the discrimination of both GP2 isoforms, a set of different murine monoclonal and camelid recombinant single domain antibodies (camelid VHH) was generated and validated in various enzyme-linked immunosorbent assay (ELISA) formats, immunofluorescence on transgenic cell lines and immunohistochemistry on monkey pancreas tissue sections. Out of six binders identified, one was validated as highly specific for GP2a. This murine monoclonal antibody (mAb) was used as capture antibody in construction of a sandwich ELISA for the detection of GP2a. Camelid VHHs or a second murine mAb served as detection antibodies in this system. All antibodies were also able to stain GP2a or GP2b on transgenic cell lines as well as on pancreatic tissue in immunohistochemistry. The KD values measured for the camelid VHHs were between 7 nM and 23pM. This set of specific binders will enable the development of suitable diagnostic tools for GP2-related studies in IBD.
Angehende Physiklehrkräfte sollen im Rahmen ihres Studiums fachliches und fachdidaktisches Wissen erwerben, welches die Gestaltung lernförderlichen Unterrichts ermöglicht. Es ist allerdings empirisch nur wenig geklärt, wie sich dieses Wissen im Laufe des Studiums entwickelt und ob es zur Ausbildung von Handlungsfähigkeiten beiträgt. Um derartige Wirkungsaussagen treffen zu können, müssen Instrumente entwickelt werden, die eine valide Testwertinterpretation zulassen. In diesem Beitrag werden auf Basis von im Projekt Profile-P+ entwickelten Instrumenten Validitätsanalysen zur längsschnittlichen Entwicklung des Professionswissens von Physiklehramtsstudierenden im Verlauf des Bachelorstudiums und ihrer Fähigkeiten zur Planung und Reflexion von Physikunterricht sowie zum Erklären von physikalischen Sachverhalten vor und nach dem Praxissemester dargestellt. Neben Wissenstests kamen standardisierte Performanztests zum Einsatz. Die vorliegenden Ergebnisse sprechen dafür, dass die erhobenen Messwerte im Sinne von Wirkungsaussagen interpretiert werden können.
For improving teacher education, there has been an increasing interest in describing teachers' professional competencies and their development in the course of implementing educational programs. The focus of the present project is on modeling and measuring domain-specific and generic competencies that future physics teachers acquire during their university studies. The model comprises characteristics and relationships between physics content knowledge, pedagogical content knowledge, and skills for explaining physics phenomena. Based on the model, assessment instruments were developed and applied as paper-and-pencil-tests and videotaped expert-novice dialogues for measuring the competencies in a large sample of physics student teachers. Trials and validation suggest that our instruments are valid in terms of content and construct validities.
Pancreatic secretory zymogen-granule membrane glycoprotein 2 (GP2) has been identified to be a major autoantigenic target in Crohn’s disease patients. It was discussed recently that a long and a short isoform of GP2 exists whereas the short isoform is often detected by GP2-specific autoantibodies. In the outcome of inflammatory bowel diseases, these GP2-specific autoantibodies are discussed as new serological markers for diagnosis and therapeutic monitoring. To investigate this further, camelid nanobodies were generated by phage display and selected against the short isoform of GP2 in order to isolate specific tools for the discrimination of both isoforms. Nanobodies are single domain antibodies derived from camelid heavy chain only antibodies and characterized by a high stability and solubility. The selected candidates were expressed, purified and validated regarding their binding properties in different enzyme-linked immunosorbent assays formats, immunofluorescence, immunohistochemistry and surface plasmon resonance spectroscopy. Four different nanobodies could be selected whereof three recognize the short isoform of GP2 very specifically and one nanobody showed a high binding capacity for both isoforms. The KD values measured for all nanobodies were between 1.3 nM and 2.3 pM indicating highly specific binders suitable for the application as diagnostic tool in inflammatory bowel disease.
Serological diagnosis and prognosis of severe acute pancreatitis by analysis of serum glycoprotein 2
(2017)
To better understand emerging adults’ perceptions of family interactions and value transmission to the next generation, we examined Hmong American emerging adults’ reflections on their parents’ parenting. Participants discussed what parenting practices they would do differently and others they hoped to emulate with their future adolescent children. Thirty Hmong American emerging adults (18-25 years; M = 21.2 years; 50% female) participated in interviews that focused retrospectively on the parent–adolescent relationship. Results revealed that emerging adults wanted to parent differently in three ways: less pressure about education, fewer restrictions, and more open communication. Emerging adults imagined being a similar
parent in four ways: promoting education, promoting life values, giving
guidance, and offering love and support. The findings highlight parenting practices that Hmong American emerging adults plan on transmitting (and not transmitting) to their own children, offering a glimpse into the type of parents the emerging adults may become.
Professional knowledge is an important source of science teachers' actions in the classroom (e.g., personal professional content knowledge [pedagogical content knowledge, PCK] is the source of enacted PCK in the refined consensus model [RCM] for PCK). However, the evidence for this claim is ambiguous at best. This study applied a cross-lagged panel design to examine the relationship between professional knowledge and actions in one particular instructional situation: explaining physics. Pre- and post a field experience (one semester), 47 preservice physics teachers from four different universities were tested for their content knowledge (CK), PCK, pedagogical knowledge (PK), and action-related skills in explaining physics. The study showed that joint professional knowledge (the weighted sum of CK, PCK, and PK scores) at the beginning of the field experience impacted the development of explaining skills during the field experience (beta = .38**). We interpret this as a particular relationship between professional knowledge and science teachers' action-related skills (enacted PCK): professional knowledge is necessary for the development of explaining skills. That is evidence that personal PCK affects enacted PCK. In addition, field experiences are often supposed to bridge the theory-practice gap by transforming professional knowledge into instructional practice. Our results suggest that for field experiences to be effective, preservice teachers should start with profound professional knowledge.