Ulrichrowe4228

Foxo1 transcription factor is an evolutionarily conserved regulator of cell metabolism, oxidative stress, inflammation, and apoptosis. Fenretinide mw Activation of Hedgehog/Gli signaling is known to regulate cell growth, differentiation, and immune function. However, the molecular mechanisms by which interactive cell signaling networks restrain oxidative stress response and necroptosis are still poorly understood. Here, we report that myeloid-specific Foxo1 knockout (Foxo1M-KO) mice were resistant to oxidative stress-induced hepatocellular damage with reduced macrophage/neutrophil infiltration, and proinflammatory mediators in liver ischemia/reperfusion injury (IRI). Foxo1M-KO enhanced β-catenin-mediated Gli1/Snail activity, and reduced receptor-interacting protein kinase 3 (RIPK3) and NIMA-related kinase 7 (NEK7)/NLRP3 expression in IR-stressed livers. Disruption of Gli1 in Foxo1M-KO livers deteriorated liver function, diminished Snail, and augmented RIPK3 and NEK7/NLRP3. Mechanistically, macrophage Foxo1 and β-catenin colocalized in the nucleus, whereby the Foxo1 competed with T-cell factor (TCF) for interaction with β-catenin under inflammatory conditions. Disruption of the Foxo1-β-catenin axis by Foxo1 deletion enhanced β-catenin/TCF binding, activated Gli1/Snail signaling, leading to inhibited RIPK3 and NEK7/NLRP3. Furthermore, macrophage Gli1 or Snail knockout activated RIPK3 and increased hepatocyte necroptosis, while macrophage RIPK3 ablation diminished NEK7/NLRP3-driven inflammatory response. Our findings underscore a novel molecular mechanism of the myeloid Foxo1-β-catenin axis in regulating Hedgehog/Gli1 function that is key in oxidative stress-induced liver inflammation and necroptosis.Adult mammalian cardiomyocytes (CM) are postmitotic, differentiated cells that cannot re-enter the cell cycle after any appreciable injury. Therefore, understanding the factors required to induce CM proliferation for repair is of great clinical importance. While expression of muscle pyruvate kinase 2 (Pkm2), a cytosolic enzyme catalyzing the final step in glycolysis, is high in end-stage heart failure (HF), the loss of Pkm2 promotes proliferation in some cellular systems, in vivo. We hypothesized that in the adult heart CM proliferation may require low Pkm2 activity. Thus, we investigated the potential for Pkm2 to regulate CM proliferation in a mouse model of myocardial infarction (MI) employing inducible, cardiac-specific Pkm2 gene knockout (Pkm2KOi) mice. We found a lack of cardiac hypertrophy or expression of the fetal gene program in Pkm2KOi mice post MI, as compared to vehicle control animals (P  less then  0.01), correlating with smaller infarct size, improved mitochondrial (mt) function, enhanced angiogenesis, reduced degree of CM apoptosis, and reduced oxidative stress post MI. There was significantly higher numbers of dividing CM in the infarct zone between 3-9 days post MI (P  less then  0.001). Mechanistically, we determined that Pkm2 interacts with β-catenin (Ctnnb1) in the cytoplasm of CM, inhibiting Ctnnb1 phosphorylation at serine 552 and tyrosine 333, by Akt. In the absence of Pkm2, Ctnnb1 translocates to the nucleus leading to transcriptional activation of proliferation-associated target genes. All these effects are abrogated by genetic co-deletion of Pkm2 and Ctnnb1. Collectively, this work supports a novel antiproliferative function for Pkm2 in CM through the sequestration of Ctnnb1 in the cytoplasm of CM whereas loss of Pkm2 is essential for CM proliferation. Reducing cardiac Pkm2 expression may provide a useful strategy for cardiac repair after MI in patients.Ubiquitination, and its control by deubiquitinating enzymes (DUBs), mediates protein stability, function, signaling and cell fate. The ovarian tumor (OTU) family DUB OTULIN (FAM105B) exclusively cleaves linear (Met1-linked) poly-ubiquitin chains and plays important roles in auto-immunity, inflammation and infection. OTULIN regulates Met1-linked ubiquitination downstream of tumor necrosis factor receptor 1 (TNFR1), toll-like receptor (TLR) and nucleotide-binding and oligomerization domain-containing protein 2 (NOD2) receptor activation and interacts with the Met1 ubiquitin-specific linear ubiquitin chain assembly complex (LUBAC) E3 ligase. However, despite extensive research efforts, the receptor and cytosolic roles of OTULIN and the distributions of multiple Met1 ubiquitin-associated E3-DUB complexes in the regulation of cell fate still remain controversial and unclear. Apart from that, novel ubiquitin-independent OTULIN functions have emerged highlighting an even more complex role of OTULIN in cellular homeostasis. For example, OTULIN interferes with endosome-to-plasma membrane trafficking and the OTULIN-related pseudo-DUB OTULINL (FAM105A) resides at the endoplasmic reticulum (ER). Here, we discuss how OTULIN contributes to cell fate control and highlight novel ubiquitin-dependent and -independent functions.Despite the emerging evidence on ferroptosis implicated in diverse pathologies, molecular linkage between oxidative inducers and chromatin as epigenetic memory carrier for its propagation remains elusive. Here, we report the identification of two WD40 proteins DCAF8 and WDR76 as substrate adapter and molecular inhibitor respectively of the Cullin-4 RING ubiquitin ligase (CRL4) system for stability control of chromatin remodeler LSH. Degradation analysis and CRL4-DCAF8 complex reconstitution demonstrate that CRL4DCAF8 is a bona fide E3 ligase for LSH. In contrast, WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of the holo-CRL4DCAF8-LSH complex assembly. Importantly, this opposing regulatory strategy is utilized in lipid hydroperoxide induced ferroptosis, where we identify key redox homeostasis genes significantly regulated by the DCAF8/WDR76/LSH axis through transcriptomic epistasis analysis. This regulation is mechanistically attributed to DNA hydroxymethylation fostered WDR76 interaction with LSH and increased ratio of DCAF8 to WDR76 for antagonistic LSH association accompanying decreased DNA oxidation along with ROS overproduction. Evaluation of epigenetic dynamics at ferroptosis gene promoters reveals linker histone H1- and LSH-associated transcriptional repression is coordinately removed upon lipid peroxidation stress. Together with the phenotypes driven by WDR76 and DCAF8 manipulations, these data identify DCAF8- and WDR76-adapted oxidative damage sensing through DNA hydroxymethylation for LSH degradation control as a crucial nexus in epigenetic regulation of ferroptosis.

Microbial keratitis (MK) is the most common non-surgical ophthalmic emergency admission in the UK. However, few prospective health-economic studies of MK have been performed, and no specific healthcare resources group (HRG) code exists. This study is designed to determine the feasibility of a data collection tool derived from the microbiology ophthalmology group (MOG) clinical record form, to enable quantification of direct costs of inpatient care, as well as prospective capture of epidemiological data relating to outcomes of MK.

Clinical, demographic and economic data were collected retrospectively between January and December 2013 for 101 consecutive patients admitted with MK, using an adaption of the MOG toolset. The direct cost of admission (COA) was calculated using national reference costs and compared to actual income to generate profit/deficit profiles for individual patients. Indices of multiple deprivation were used to assess effect of deprivation on the COA.

The total income generated through are able to self-administer treatment after the sterilisation phase. The MOG-derived data collection toolset captures pertinent clinical data for quantification of COA. Further development into a multiuser and multisite platform is required for robust prospective testing, together with expansion to capture indirect costs of disease burden, including impact of treatment, visual morbidity and quality of life.Modern electrochemical energy conversion devices require more advanced proton conductors for their broad applications. Phosphonated polymers have been proposed as anhydrous proton conductors for fuel cells. However, the anhydride formation of phosphonic acid functional groups lowers proton conductivity and this prevents the use of phosphonated polymers in fuel cell applications. Here, we report a poly(2,3,5,6-tetrafluorostyrene-4-phosphonic acid) that does not undergo anhydride formation and thus maintains protonic conductivity above 200 °C. We use the phosphonated polymer in fuel cell electrodes with an ion-pair coordinated membrane in a membrane electrode assembly. This synergistically integrated fuel cell reached peak power densities of 1,130 mW cm-2 at 160 °C and 1,740 mW cm-2 at 240 °C under H2/O2 conditions, substantially outperforming polybenzimidazole- and metal phosphate-based fuel cells. Our result indicates a pathway towards using phosphonated polymers in high-performance fuel cells under hot and dry operating conditions.Solid-state thermoelectric devices can directly convert electricity into cooling or enable heat pumping through the Peltier effect. The commercialization of thermoelectric cooling technology has been built on the Bi2Te3 alloys, which have had no rival for the past six decades around room temperature. With the discovery and development of more promising materials, it is possible to reshape thermoelectric cooling technology. Here we review the current status of, and future outlook for, thermoelectric cooling materials.DNA nanotechnology is an emerging field that promises fascinating opportunities for the manipulation and imaging of proteins on a cell surface. The key to progress is the ability to create a nucleic acid-protein junction in the context of living cells. Here we report a covalent labelling reaction that installs a biostable peptide nucleic acid (PNA) tag. The reaction proceeds within minutes and is specific for proteins carrying a 2 kDa coiled-coil peptide tag. Once installed, the PNA label serves as a generic landing platform that enables the recruitment of fluorescent dyes via nucleic acid hybridization. We demonstrate the versatility of this approach by recruiting different fluorophores, assembling multiple fluorophores for increased brightness and achieving reversible labelling by way of toehold-mediated strand displacement. Additionally, we show that labelling can be carried out using two different coiled-coil systems, with epidermal growth factor receptor and endothelin receptor type B, on both HEK293 and CHO cells. Finally, we apply the method to monitor internalization of epidermal growth factor receptor on CHO cells.Photoinduced charge-transfer is an important process in nature and technology and is responsible for the emergence of exotic functionalities, such as magnetic order for cyanide-bridged bimetallic coordination networks. Despite its broad interest and intensive developments in chemistry and material sciences, the atomic-scale description of the initial photoinduced process, which couples intermetallic charge-transfer and spin transition, has been debated for decades; it has been beyond reach due to its extreme speed. Here we study this process in a prototype cyanide-bridged CoFe system by femtosecond X-ray and optical absorption spectroscopies, enabling the disentanglement of ultrafast electronic and structural dynamics. Our results demonstrate that it is the spin transition that occurs first on the Co site within ~50 fs, and it is this that drives the subsequent Fe-to-Co charge-transfer within ~200 fs. This study represents a step towards understanding and controlling charge-transfer-based functions using light.