Evaluating the Patient-Reported Outcomes Measurement Information System scales in acute intermittent porphyria.

PurposeAcute intermittent porphyria (AIP) is a rare inborn error of heme biosynthesis characterized by life-threatening acute attacks. Few studies have assessed quality of life (QoL) in AIP and those that have had small sample sizes and used tools that may not have captured important domains.MethodsBaseline data from the Porphyrias Consortium's Longitudinal Study were obtained for 259 patients, including detailed disease and medical history data, and the following Patient-Reported Outcomes Measurement Information System (PROMIS) scales: anxiety, depression, pain interference, fatigue, sleep disturbance, physical function, and satisfaction with social roles. Relationships between PROMIS scores and clinical and biochemical AIP features were explored.ResultsPROMIS scores were significantly worse than the general population across all domains, except depression. Each domain discriminated well between asymptomatic and symptomatic patients with symptomatic patients having worse scores. Many important clinical variables like symptom frequency were significantly associated with domain scores in univariate analyses, showing responsiveness of the scales, specifically pain interference and fatigue. However, most regression models only explained ~20% of the variability observed in domain scores.ConclusionPain interference and fatigue were the most responsive scales in measuring QoL in this AIP cohort. Future studies should assess whether these scales capture longitudinal disease progression and treatment response

Chronic Activation of Hepatic Nrf2 Has No Major Effect on Fatty Acid and Glucose Metabolism in Adult Mice

The transcription factor NF-E2-related factor 2 (Nrf2) induces cytoprotective genes, but has also been linked to the regulation of hepatic energy metabolism. In order to assess the pharmacological potential of hepatic Nrf2 activation in metabolic disease, Nrf2 was activated over 7 weeks in mice on Western diet using two different siRNAs against kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2. Whole genome expression analysis followed by pathway analysis demonstrated successful knock-down of Keap1 expression and induction of Nrf2-dependent genes involved in anti- oxidative stress defense and biotransformation, proving the activation of Nrf2 by the siRNAs against Keap1. Neither the expression of fatty acid- nor carbohydrate-handling proteins was regulated by Keap1 knock-down. Metabolic profiling of the animals did also not show effects on plasma and hepatic lipids, energy expenditure or glucose tolerance. The data indicate that hepatic Keap1/Nrf2 is not a major regulator of glucose or lipid metabolism in mice

Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein

The activation of at least 23 different mammalian kinases requires the phosphorylation of their hydrophobic motifs by the kinase PDK1. A linker connects the phosphoinositide-binding PH domain to the catalytic domain, which contains a docking site for substrates called the PIF pocket. Here, we used a chemical biology approach to show that PDK1 existed in equilibrium between at least three distinct conformations with differing substrate specificities. The inositol polyphosphate derivative HYG8 bound to the PH domain and disrupted PDK1 dimerization by stabilizing a monomeric conformation in which the PH domain associated with the catalytic domain and the PIF pocket was accessible. In the absence of lipids, HYG8 potently inhibited the phosphorylation of Akt (also termed PKB) but did not affect the intrinsic activity of PDK1 or the phosphorylation of SGK, which requires docking to the PIF pocket. In contrast, the small molecule valsartan bound to the PIF pocket and stabilized a second distinct monomeric conformation. Our study reveals dynamic conformations of full-length PDK1 in which the location of the linker and the PH domain relative to the catalytic domain determines the selective phosphorylation of PDK1 substrates. The study further suggests new approaches for the design of drugs to selectively modulate signaling downstream of PDK1

Multiple gender cultures: gender as an epistemic test case of plural modernities

Winkel H. Multiple gender cultures: gender as an epistemic test case of plural modernities. In: Winkel H, Poferl A, eds. Multiple Gender Cultures, Sociology and Plural Modernities. Re-reading Social Constructions of Gender across the Globe in a Decolonial Perspective. New York: Routledge; 2021: 225-264

Re-reading Social Constructions of Gender across the Globe in a Decolonial Perspective

Winkel H, Poferl A, eds. Multiple Gender Cultures, Sociology, and Plural Modernities . 1st ed. New York: Routledge; 2021

Eine Neubestimmung des Verhältnisses von Feminismus, Säkularismus und Religion. Zur Einleitung

Winkel H, Poferl A. Eine Neubestimmung des Verhältnisses von Feminismus, Säkularismus und Religion. Zur Einleitung. Feministische Studien. 2021;39(1):3-16

im Gespräch mit Ulrike Freitag, Yael Kupferberg, Nahed Samour und Dorothea Sattler (2021): Das Spannungsverhältnis von Feminismus, Säkularismus und Religion

Winkel H, Poferl A. im Gespräch mit Ulrike Freitag, Yael Kupferberg, Nahed Samour und Dorothea Sattler (2021): Das Spannungsverhältnis von Feminismus, Säkularismus und Religion. Feministische Studien. 2021;39(1):104-127

Citizenship, Transnational Migration and the Gendering of Modern/Colonial Inequalities

Roth J. Citizenship, Transnational Migration and the Gendering of Modern/Colonial Inequalities. In: Winkel H, Poferl A, eds. Multiple Gender Cultures, Sociology and Plural Modernities. Re-reading Social Constructions of Gender across the Globe in a De-Colonial Perspective. Routledge; 2021: 62-81

Feminismus, Säkularismus, Religion

Winkel H, Poferl A, Oloff A, eds. Feminismus, Säkularismus, Religion. Feministische Studien. 2021;39(1)