High MLL5 expression levels are associated with a favorable outcome and may improve risk and treatment stratification in AML.

The “free radical theory of aging” suggests that reactive oxygen species (ROS) are responsible for age‐related loss of cellular functions and, therefore, represent the main cause of aging. Redox regulation by thioredoxin‐1 (TRX) plays a crucial role in responses to oxidative stress. We show that thioredoxin‐interacting protein (TXNIP), a negative regulator of TRX, plays a major role in maintaining the redox status and, thereby, influences aging processes. This role of TXNIP is conserved from flies to humans. Age‐dependent upregulation of TXNIP results in decreased stress resistance to oxidative challenge in primary human cells and in Drosophila. Experimental overexpression of TXNIP in flies shortens lifespan due to elevated oxidative DNA damage, whereas downregulation of TXNIP enhances oxidative stress resistance and extends lifespan.

Constitutively active NFκB promotes survival of many cancers, especially T-cell lymphomas and leukemias by upregulating antiapoptotic proteins such as inhibitors of apoptosis (IAPs) and FLICE-like inhibitory proteins (cFLIPs).Nuclear factor-κ B (NFκ B) is a central transcription factor orchestrating innate and adaptive immune responses. In acute inflammation, NFκ B activity is tightly regulated. However, aberrantly activated NFκ B is associated with chronic inflammatory diseases and a variety of human cancers including both solid and hematopoietic malignancies. Cancers such as T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), and its leukemic variant, Sézary Syndrome, revealed constitutive NFκ B activity [1][2][3][4] .The NFκ B family consists of five Rel related proteins: RelA (p65), RelB, cRel, p50 and p52, which can form both homo-and heterodimers. The typical NFκ B complex is a p65/p50 heterodimer critical for NFκ B mediated anti-apoptotic effects 5 . In its inactive form, NFκ B is sequestered in the cytoplasm by Iκ Bα . Phosphorylation and proteasomal degradation of Iκ Bα releases NFκ B. Subsequent nuclear translocation and full activation of NFκ B is redox-dependent and mediated by phosphorylation 6 . The redox regulator Thioredoxin-1 (Trx1) promotes DNA binding activity of NFκ B by reduction of a cysteine residue within its DNA binding domain 7,8 . During oncogenesis, NFκ B promotes cell survival and proliferation by inducing expression of molecules associated with suppression of programmed cell death (PCD), such as cFLIPs 9 , IAP proteins 6,10 , and members of the Bcl-2 family 11 . PCD is a mechanism of tumor suppression and manifests itself in, e.g. apoptosis and necroptosis. Necroptosis is a form of regulated necrosis, which has been implicated to trigger strong immune responses by release of damage-associated molecular patterns (DAMPs) 12 . Moreover, necroptosis is critical for T-cell homeostasis as backup to eliminate an excess of activated T-cells after clonal expansion preventing autoimmunity 13 .The ripoptosome is a signaling platform triggering cell death in an apoptotic or necroptotic manner [14][15][16] . The core components of the ripoptosome include caspase-8, FADD (Fas-associated death domain) and RIPK1 (Receptor-interacting kinase 1). Formation and activation of the ripoptosome are negatively regulated by IAPs (cIAP1, cIAP2 and XIAP) and cFLIPs (cFLIP L and cFLIP S ), respectively. IAPs are regulated by Smac (Second

Background: Equipment of the neuronal plasma membrane with ion channels is regulated by translocation of ion channel subunits. Results: Analysis of chimeric ion channels composed of Drosophila channels TRP and TRPL revealed Ca 2ϩ -dependent translocation of TRPL and chimera containing N-and C-terminal regions of TRPL. Conclusion:The translocation of the TRPL channel requires both the N-and C-terminal regions together with sustained Ca 2ϩ entry. Significance: The results have implications for understanding subcellular trafficking of TRP family members.In Drosophila photoreceptors the transient receptor potential-like (TRPL), but not the TRP channels undergo light-dependent translocation between the rhabdomere and cell body. Here we studied which of the TRPL channel segments are essential for translocation and why the TRP channels are required for inducing TRPL translocation. We generated transgenic flies expressing chimeric TRP and TRPL proteins that formed functional light-activated channels. Translocation was induced only in chimera containing both the N-and C-terminal segments of TRPL. Using an inactive trp mutation and overexpressing the Na ؉ / Ca 2؉ exchanger revealed that the essential function of the TRP channels in TRPL translocation is to enhance Ca 2؉ -influx. These results indicate that motifs present at both the N and C termini as well as sustained Ca 2؉ entry are required for proper channel translocation.The physiological properties of cells are largely determined by a specific set of ion channels at the plasma membrane. Besides regulation at the gene expression level, trafficking of ion channels into and out of the plasma membrane has been established as an important mechanism for manipulating the number of channels at a specific cellular site (for reviews see Refs. 1, 2). For instance, the translocation of AMPA-type glutamate receptors from endosomal membranes into the synapses of hippocampal and lateral amygdala neurons underlies the formation of long-term potentiation and is thus involved in associative learning (3,4). Regulation by controlled insertion and internalization of ion channels has also been studied for a number of vertebrate transient receptor potential (TRP) 4 channels and for the Drosophila TRPL channel (see Refs. 5,6). TRP channels function in sensory systems such as invertebrate photoreceptors, mechanoreceptors, pheromone receptors, taste receptors, pain receptors or receptors for detection of hot and cold temperature, but also as regulators of ion homeostasis in nonneuronal cells (see . The TRP channel superfamily is classified into seven related subfamilies designated TRPC (canonical or classical), in which the Drosophila TRP and TRPL are members, TRPM (Melastatin), TRPN (NompC), TRPV (Vanilloid receptor), TRPA (ANKTM1), TRPP (Polycystin), and TRPML (Mucolipin, for reviews see Refs. 12, 13). Regulated subcellular translocation has been reported for TRPV1 and TRPV2 that are translocated from an internal compartment to the plasma membrane upon hormonal stimulation with nerve gro...

Introduction: In peritoneal dialysis (PD) patients, the peritoneal membrane is affected by glucose-based solutions used as peritoneal dialysate fluids. This exposure leads to changes of the membrane which may eventually culminate in fibrosis and method failure. In vitro or animal studies demonstrated that glucose transporters are upregulated upon exposure to these solutions. Expression studies of glucose transporters in human peritoneum have not been reported yet. Methods: Expression of SGLT-2, GLUT1, and GLUT3 in human peritoneal biopsies was analyzed by real-time polymerase chain reaction and Western blot analysis. The localization of these glucose transporters in the peritoneum was evaluated by immunohistochemistry using a Histo-Score. Results: Peritoneal biopsies of patients (healthy controls, uremic, PD, and encapsulating peritoneal sclerosis [EPS]) were analyzed. We found evidence of SGLT-2, GLUT1, and GLUT3 expression in the peritoneal membrane. Protein expression of SGLT-2 increases with PD duration and is significantly enhanced in EPS patients. All transporters were predominantly, but not exclusively, located adjacent to the vessel walls of the peritoneal membrane. Conclusion: Our study showed that SGLT-2, GLUT1, and GLUT3 were regularly expressed in the human peritoneum. SGLT-2 was particularly upregulated in PD patients with EPS, suggesting that this upregulation may be associated with pathological changes in the peritoneal membrane in this syndrome. Since preclinical studies in mice show that SGLT-2 inhibitors or downregulation of SGLT-2 ameliorated pathological changes in the peritoneum, SGLT-2 inhibitors may be potentially promising agents for therapy in PD patients that could reduce glucose absorption and delay functional deterioration of the peritoneal membrane in the long term.

Background: Drosophila TRPL is a cation channel of the phototransduction cascade that undergoes light-dependent subcellular translocation between cell compartments. Results: Drosophila TRPL exhibits a light-dependent phosphorylation pattern required for its stable localization in the rhabdomere of photoreceptor cells. Conclusion: Multiple phosphorylation sites control localization and stability of TRPL. Significance: A member of the TRP ion channel family displays a complex phosphorylation pattern with functional relevance.

<b><i>Background:</i></b> Acute kidney injury (AKI) is associated with high morbidity and mortality; therefore, prevention is important. The aim of this study was to systematically assess AKI incidence after cardiac surgery as documented in clinical routine compared to the real incidence because AKI may be under-recognized in clinical practice. Further, its postoperative management was compared to Kidney Disease: Improving Global Outcomes (KDIGO) recommendations because recognition and adequate treatment represent the fundamental cornerstone in the prevention and management of AKI. <b><i>Methods:</i></b> This retrospective single-center study included <i>n</i> = 100 patients who underwent cardiac surgery with cardiopulmonary bypass. The coded incidence of postoperative AKI during intensive care unit stay after surgery was compared to the real AKI incidence. Furthermore, conformity of postoperative parameters with KDIGO recommendations for AKI prevention and management was reviewed. <b><i>Results:</i></b> We found a considerable discrepancy between coded and real incidence, and conformity with KDIGO recommendations was found to be relatively low. The coded incidence was significantly lower (<i>n</i> = 12 vs. <i>n</i> = 52, <i>p</i> &#x3c; 0.05), representing a coding rate of 23.1%. Regarding postoperative management, 90% of all patients had at least 1 episode with mean arterial pressure &#x3c;65 mm Hg within the first 72 h. Furthermore, regarding other preventive parameters (avoiding hyperglycemia, stopping angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, avoiding contrast media, and nephrotoxic drugs), only 10 patients (20.8%) in the non-AKI group and in 5 (9.6%) subjects in the AKI group had none of all the above potential AKI-promoting factors. <b><i>Conclusions:</i></b> AKI recognition in everyday clinical routine seems to be low, especially in lower AKI stages, and the current postoperative management still offers potential for optimization. Possibly, higher AKI awareness and stricter postoperative management could already achieve significant effects in prevention and treatment of AKI.

SummaryFamily members of the cationic transient receptor potential (TRP) channels serve as sensors and transducers of environmental stimuli. The ability of different TRP channel isoforms of specific subfamilies to form heteromultimers and the structural requirements for channel assembly are still unresolved. Although heteromultimerization of different mammalian TRP channels within single subfamilies has been described, even within a subfamily (such as TRPC) not all members co-assemble with each other. In Drosophila photoreceptors two TRPC channels, TRP and TRP-like protein (TRPL) are expressed together in photoreceptors where they generate the light-induced current. The formation of functional TRP-TRPL heteromultimers in cell culture and in vitro has been reported. However, functional in vivo assays have shown that each channel functions independently of the other. Therefore, the issue of whether TRP and TRPL form heteromultimers in vivo is still unclear. In the present study we investigated the ability of TRP and TRPL to form heteromultimers, and the structural requirements for channel assembly, by studying assembly of GFP-tagged TRP and TRPL channels and chimeric TRP and TRPL channels, in vivo. Interaction studies of tagged and native channels as well as native and chimeric TRP-TRPL channels using coimmunoprecipitation, immunocytochemistry and electrophysiology, critically tested the ability of TRP and TRPL to interact. We found that TRP and TRPL assemble exclusively as homomultimeric channels in their native environment. The above analyses revealed that the transmembrane regions of TRP and TRPL do not determine assemble specificity of these channels. However, the C-terminal regions of both TRP and TRPL predominantly specify the assembly of homomeric TRP and TRPL channels.