610 Medizin und Gesundheit
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The impact of the appropriate and inappropriately applied statistical metrics to verify the State of Control of pharmaceutical manufacturing has been reviewed from an auditor’s perspective. Good and bad statistical practices have been presented in an attempt for manufactures to appreciate the risks of using these metrics. Conclusions concerning (1) control charts to be used instead of line/run charts for trend analysis, (2) Ppk as the preferred capability index (but still with an ambition to get processes into statistical control), (3) show process capability indices along with their respective control charts (4) determine which Manufacturing State of Control the product/process lies in (5) an effective Control Strategy can only be implemented if the Manufacturing State of Control is understood, (6) when presenting data consider what is truly representative of the product/process and not the average (7) Management should align with ICH Q10 more effectively to provide statistical resources for their personnel.
Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.
YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.
Formation of the anteroposterior and dorsoventral body axis in the Caenorhabditis elegans embryo depends on cortical actomyosin flows and advection of polarity determinants. The role of this patterning mechanism in tissue polarization immediately after formation of cell-cell contacts is not fully understood. Here, we demonstrate that planar cell polarity (PCP) is established in the C. elegans embryo at the time of left-right (l/r) symmetry breaking. At this stage, centripetal cortical flows asymmetrically and differentially advect anterior polarity determinants (aPARs) PAR-3, PAR-6 and PKC-3 from cell-cell contacts to the medial cortex, which results in their unmixing from apical myosin. Advection generally requires GSK-3 and CDC-42, while advection of PAR-6 specifically depends on the RhoGAP PAC-1. Concurrent asymmetric retention of PAR-3, E-cadherin/HMR-1, PAC-1 and opposing retention of the antagonistic Wnt pathway components APC/APR-1 and Frizzled/MOM-5 at apical cell-cell contacts leads to planar asymmetries. The most obvious mark of PCP, asymmetric retention of PAR-3 at posterior cell-cell contacts on the left side of the embryo, is required for proper cytokinetic cell intercalation. Hence, our data uncover how PCP can be established through Wnt signaling as well as dissociation and planar asymmetric retention of aPARs mediated by distinct Rho GTPases and their regulators.
The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification
(2019)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Ubiquitination is a widespread post-translational modification that controls multiple steps in autophagy, a major lysosome-mediated intracellular degradation pathway. A variety of ubiquitin chains are attached as selective labels on protein aggregates and dysfunctional organelles, thus promoting their autophagy-dependent degradation. Moreover, ubiquitin modification of autophagy regulatory components is essential to positively or negatively regulate autophagy flux in both non-selective and selective pathways. We review the current findings that elucidate the components, timing, and kinetics of the multivalent role of ubiquitin signals in control of amplitude and selectivity of autophagy pathways as well as their impact on the development of human diseases.
Ubiquitin-binding modules are constituents of cellular proteins that mediate the effects of ubiquitylation by making transient, non-covalent interactions with ubiquitin molecules. While some ubiquitin-binding modules bind single ubiquitin moieties, others are selective for specific ubiquitin chains of different linkage types and lengths. In recent years, functions of ubiquitin chains that are polymerized through their Lys or N-terminal Met (i.e. linear chains) residues have been linked to a variety of cellular processes. Selectivity of ubiquitin-binding modules for different ubiquitin chain types appears as a key to the distinct regulatory consequences during protein quality control pathways, receptor endocytosis, gene transcription, signaling via the NF-κB pathway, and autophagy.