Inducible cAMP Early Repressor Regulates Corticosterone Suppression after Tricyclic Antidepressant Treatment

The cAMP-response element binding protein (CREB) is involved in antidepressant action, but the role of related CRE-binding transcription factors in the behavioral and endocrine responses to antidepressants is unclear. Alternative transcription of the cAMP response element-modulator (CREM) gene yields activator and repressor isoforms, including the strong repressor induciblecAMPearly repressor (ICER). ICER is highly expressed in hypothalamic tissues and upregulated after electroconvulsive seizure. Thus, ICER may be a novel mediator of antidepressant action at endocrine and/or behavioral levels. Here we establish that both subchronic and chronic desipramine (DMI) treatments upregulate hypothalamic ICER expression in wild-type mice. Behavioral responses to DMI in the forced swim and tail suspension tests are unchanged in mice lacking ICER. However, the ability of DMI to suppress an acute corticosterone response after swim stress is compromised in ICER-deficient mice, suggesting that increased hypothalamic ICER mRNA after DMI treatment may be required for suppression of corticosterone release. To investigate the mechanism underlying this response, we measured corticotropin releasing factor (CRF), an upstream modulator of corticosterone release. Using real-time quantitative PCR, we establish that hypothalamic CRF expression is significantly reduced after swim exposure in DMI-treated wild-type mice, however DMI is unable to blunt hypothalamic CRF expression in ICER-deficient mice. Furthermore, we demonstrate that ICER is enriched in CRF-expressing neurons in the paraventricular nucleus of the hypothalamus. These data indicate that ICER is required for DMI to reduce stress-induced corticosterone release through regulation of hypothalamic CRF expression, revealing a novel role for ICER in antidepressant regulation of the hypothalamic–pituitary adrenal axis

Correction:Transgenic expression of the dicotyledonous pattern recognition receptor EFR in rice leads to ligand-dependent activation of defense responses

[This corrects the article DOI: 10.1371/journal.ppat.1004809.]

Transgenic expression of the dicotyledonous pattern recognition receptor EFR in rice leads to ligand-dependent activation of defense responses

Plant plasma membrane localized pattern recognition receptors (PRRs) detect extracellular pathogen-associated molecules. PRRs such as Arabidopsis EFR and rice XA21 are taxonomically restricted and are absent from most plant genomes. Here we show that rice plants expressing EFR or the chimeric receptor EFR::XA21, containing the EFR ectodomain and the XA21 intracellular domain, sense both Escherichia coli- and Xanthomonas oryzae pv. oryzae (Xoo)-derived elf18 peptides at sub-nanomolar concentrations. Treatment of EFR and EFR::XA21 rice leaf tissue with elf18 leads to MAP kinase activation, reactive oxygen production and defense gene expression. Although expression of EFR does not lead to robust enhanced resistance to fully virulent Xoo isolates, it does lead to quantitatively enhanced resistance to weakly virulent Xoo isolates. EFR interacts with OsSERK2 and the XA21 binding protein 24 (XB24), two key components of the rice XA21-mediated immune response. Rice-EFR plants silenced for OsSERK2, or overexpressing rice XB24 are compromised in elf18-induced reactive oxygen production and defense gene expression indicating that these proteins are also important for EFR-mediated signaling in transgenic rice. Taken together, our results demonstrate the potential feasibility of enhancing disease resistance in rice and possibly other monocotyledonous crop species by expression of dicotyledonous PRRs. Our results also suggest that Arabidopsis EFR utilizes at least a subset of the known endogenous rice XA21 signaling components

Data acquisition and monitoring for the KLOE detector

none77siThe Data Acquisition system for the KLOE experiment, presently running at the Laboratori Nazionali di Frascati DAPhiNE collider, has been designed to sustain an acquisition throughput of 50 Mbyte/s for an event rate of 10 kHz. its two major components are the front end data readout, based on custom buses, and a complex network of computers and storage devices hosting a set of distributed processes. The end result is a seamless data transport from the readout system to the storage library, accompanied by concurrent on line calibrations and data quality control.openA. ALOISIO; F. AMBROSINO; S. CAVALIERE; F. CEVENINI; C. DI DONATO; A. DORIA; D. FIORE; L. MEROLA; G. PIROZZI; G. SARACINO; M. ANTONELLI; F. BOSSI; P. CIAMBRONE; P. DE SIMONE; S. DELL'AGNELLO; M.L. FERRER; G. FINOCCHIARO; C. FORTI; C. GATTI; S. GIOVANNELLA; W. GRANDEGGER; G. LANFRANCHI; B. MARTINI; W. MEI; S. MISCETTI; M. MOULSON; F. MURTAS; M. PALUTAN; L. PASSALACQUA; F. PELUCCHI; P. SANTANGELO; B. SCIASCIA; I. SFILIGOI; J. SHAN; T. SPADARO; P. VALENTE; Y ZHOU; C. BINI; V. BOCCI; G. CABIBBO; R. CALOI; A. CARDINI; E. DE LUCIA; A. DI DOMENICO; P. GAUZZI; E. PASQUALUCCI; M. PASSASEO; D. PICCA; L. PONTECORVO; E. VALENTE; S. VENEZIANO; P. BRANCHINI; E. GRAZIANI; A. PASSERI; A. FERRARI; E. SPIRITI; C. STANESCU; L. TORTORA; M. CASARSA; G. CATALDI; E. GORINI; M. PRIMAVERA; A. VENTURA; G. DE ROBERTIS; P. GUARNACCIA; A. DENIG; CHEN-CHENG KUO; S. MULLER; B. VALERIANI; S. DI FALCO; M. INCAGLI; G. VENANZONI; R. MESSI; L. PACCIANI; E. SANTOVETTI; J. LEE-FRANZINI; M. MARTEMIANOVA., Aloisio; F., Ambrosino; S., Cavaliere; F., Cevenini; C., DI DONATO; A., Doria; D., Fiore; L., Merola; G., Pirozzi; G., Saracino; M., Antonelli; F., Bossi; P., Ciambrone; P., DE SIMONE; S., Dell'Agnello; M. L., Ferrer; G., Finocchiaro; C., Forti; C., Gatti; S., Giovannella; W., Grandegger; G., Lanfranchi; B., Martini; W., Mei; S., Miscetti; M., Moulson; F., Murtas; M., Palutan; L., Passalacqua; F., Pelucchi; P., Santangelo; B., Sciascia; I., Sfiligoi; J., Shan; T., Spadaro; P., Valente; Y., Zhou; C., Bini; V., Bocci; G., Cabibbo; R., Caloi; A., Cardini; E., DE LUCIA; A., DI DOMENICO; P., Gauzzi; E., Pasqualucci; M., Passaseo; D., Picca; L., Pontecorvo; E., Valente; S., Veneziano; P., Branchini; E., Graziani; A., Passeri; A., Ferrari; E., Spiriti; C., Stanescu; L., Tortora; M., Casarsa; G., Cataldi; Gorini, Edoardo; Primavera, Margherita; Ventura, Andrea; G., DE ROBERTIS; P., Guarnaccia; A., Denig; CHEN CHENG, Kuo; S., Muller; B., Valeriani; S., DI FALCO; M., Incagli; G., Venanzoni; R., Messi; L., Pacciani; E., Santovetti; J., LEE FRANZINI; M., Martemiano

O-GlcNAcylation and oxidation of proteins: is signalling in the cardiovascular system becoming sweeter?

O-GlcNAcylation is an unusual form of protein glycosylation, where a single-sugar [GlcNAc (N-acetylglucosamine)] is added (via β-attachment) to the hydroxyl moiety of serine and threonine residues of nuclear and cytoplasmic proteins. A complex and extensive interplay exists between O-GlcNAcylation and phosphorylation. Many phosphorylation sites are also known glycosylation sites, and this reciprocal occupancy may produce different activities or alter the stability in a target protein. The interplay between these two post-translational modifications is not always reciprocal, as some proteins can be concomitantly phosphorylated and O-GlcNAcylated, and the adjacent phosphorylation or O-GlcNAcylation can regulate the addition of either moiety. Increased cardiovascular production of ROS (reactive oxygen species), termed oxidative stress, has been consistently reported in various chronic diseases and in conditions where O-GlcNAcylation has been implicated as a contributing mechanism for the associated organ injury/protection (for example, diabetes, Alzheimer's disease, arterial hypertension, aging and ischaemia). In the present review, we will briefly comment on general aspects of O-GlcNAcylation and provide an overview of what has been reported for this post-translational modification in the cardiovascular system. We will then specifically address whether signalling molecules involved in redox signalling can be modified by O-GlcNAc (O-linked GlcNAc) and will discuss the critical interplay between O-GlcNAcylation and ROS generation. Experimental evidence indicates that the interactions between O-GlcNAcylation and oxidation of proteins are important not only for cell regulation in physiological conditions, but also under pathological states where the interplay may become dysfunctional and thereby exacerbate cellular injury

Antimicrobials: A Global Alliance For Optimizing Their Rational Use In Intra-abdominal Infections (agora)

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs.11NIAID NIH HHS [R01 AI117211

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA)

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs

Complicated intra-abdominal infections worldwide : the definitive data of the CIAOW Study

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