A-Kinase Anchoring in Dendritic Cells Is Required for Antigen Presentation

BACKGROUND: Dendritic cells (DC) are the most potent antigen presenting cells (APC) of the immune system. Prostaglandin E(2), cyclic AMP, and protein kinase A (PKA) have all been shown to regulate DC maturation and activity. In other cells, the ability of these molecules to convey their signals has been shown to be dependent on A-kinase anchoring proteins (AKAPs). Here we present evidence for the existence and functional importance of AKAPs in human DC. METHODOLOGY/PRINCIPAL FINDINGS: Using immunofluorescence and/or western analyses we identify AKAP79, AKAP149, AKAP95, AKAP LBC and Ezrin. We also demonstrate by western analysis that expression of AKAP79, AKAP149 and RII are upregulated with DC differentiation and maturation. We establish the functional importance of PKA anchoring in multiple aspects of DC biology using the anchoring inhibitor peptides Ht31 and AKAP-IS. Incubation of protein or peptide antigen loaded DC with Ht31 or AKAP-IS results in a 30-50% decrease in antigen presentation as measured by IFN-gamma production from antigen specific CD4(+) T cells. Incubation of LPS treated DC with Ht31 results in 80% inhibition of TNF-alpha and IL-10 production. Ht31 slightly decreases the expression of CD18 and CD11a and CD11b, slightly increases the basal expression of CD83, dramatically decreases the LPS stimulated expression of CD40, CD80 and CD83, and significantly increases the expression of the chemokine receptor CCR7. CONCLUSIONS: These experiments represent the first evidence for the functional importance of PKA anchoring in multiple aspects of DC biology

Epidemiologic and clinical updates on impulse control disorders: a critical review

The article reviews the current knowledge about the impulse control disorders (ICDs) with specific emphasis on epidemiological and pharmacological advances. In addition to the traditional ICDs present in the DSM-IV—pathological gambling, trichotillomania, kleptomania, pyromania and intermittent explosive disorder—a brief description of the new proposed ICDs—compulsive–impulsive (C–I) Internet usage disorder, C–I sexual behaviors, C–I skin picking and C–I shopping—is provided. Specifically, the article summarizes the phenomenology, epidemiology and comorbidity of the ICDs. Particular attention is paid to the relationship between ICDs and obsessive–compulsive disorder (OCD). Finally, current pharmacological options for treating ICDs are presented and discussed

The First Post-Kepler Brightness Dips of KIC 8462852

We present a photometric detection of the first brightness dips of the unique variable star KIC 8462852 since the end of the Kepler space mission in 2013 May. Our regular photometric surveillance started in October 2015, and a sequence of dipping began in 2017 May continuing on through the end of 2017, when the star was no longer visible from Earth. We distinguish four main 1-2.5% dips, named "Elsie," "Celeste," "Skara Brae," and "Angkor", which persist on timescales from several days to weeks. Our main results so far are: (i) there are no apparent changes of the stellar spectrum or polarization during the dips; (ii) the multiband photometry of the dips shows differential reddening favoring non-grey extinction. Therefore, our data are inconsistent with dip models that invoke optically thick material, but rather they are in-line with predictions for an occulter consisting primarily of ordinary dust, where much of the material must be optically thin with a size scale <<1um, and may also be consistent with models invoking variations intrinsic to the stellar photosphere. Notably, our data do not place constraints on the color of the longer-term "secular" dimming, which may be caused by independent processes, or probe different regimes of a single process

A Biphasic and Brain-Region Selective Down-Regulation of Cyclic Adenosine Monophosphate Concentrations Supports Object Recognition in the Rat

Background: We aimed to further understand the relationship between cAMP concentration and mnesic performance. Methods and Findings: Rats were injected with milrinone (PDE3 inhibitor, 0.3 mg/kg, i.p.), rolipram (PDE4 inhibitor, 0.3 mg/ kg, i.p.) and/or the selective 5-HT4R agonist RS 67333 (1 mg/kg, i.p.) before testing in the object recognition paradigm. Cyclic AMP concentrations were measured in brain structures linked to episodic-like memory (i.e. hippocampus, prefrontal and perirhinal cortices) before or after either the sample or the testing phase. Except in the hippocampus of rolipram treated-rats, all treatment increased cAMP levels in each brain sub-region studied before the sample phase. After the sample phase, cAMP levels were significantly increased in hippocampus (1.8 fold), prefrontal (1.3 fold) and perirhinal (1.3 fold) cortices from controls rat while decreased in prefrontal cortex (,0.83 to 0.62 fold) from drug-treated rats (except for milrinone+RS 67333 treatment). After the testing phase, cAMP concentrations were still increased in both the hippocampus (2.76 fold) and the perirhinal cortex (2.1 fold) from controls animals. Minor increase were reported in hippocampus and perirhinal cortex from both rolipram (respectively, 1.44 fold and 1.70 fold) and milrinone (respectively 1.46 fold and 1.56 fold)-treated rat. Following the paradigm, cAMP levels were significantly lower in the hippocampus, prefrontal and perirhinal cortices from drug-treated rat when compared to controls animals, however, only drug-treated rats spent longer time exploring the novel object during the testing phase (inter-phase interval of 4 h)

Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption

To prevent dehydration, terrestrial animals and humans have developed a sensitive and versatile system to maintain their water homeostasis. In states of hypernatremia or hypovolemia, the antidiuretic hormone vasopressin (AVP) is released from the pituitary and binds its type-2 receptor in renal principal cells. This triggers an intracellular cAMP signaling cascade, which phosphorylates aquaporin-2 (AQP2) and targets the channel to the apical plasma membrane. Driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels. When water homeostasis is restored, AVP levels decline, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again. The action of AVP is counterbalanced by several hormones like prostaglandin E2, bradykinin, dopamine, endothelin-1, acetylcholine, epidermal growth factor, and purines. Moreover, AQP2 is strongly involved in the pathophysiology of disorders characterized by renal concentrating defects, as well as conditions associated with severe water retention. This review focuses on our recent increase in understanding of the molecular mechanisms underlying AVP-regulated renal water transport in both health and disease

V392 Persei: a γ-ray bright nova eruption from a known dwarf nova

V392 Persei is a known dwarf nova (DN) that underwent a classical nova eruption in 2018. Here we report ground-based optical, Swift UV and X-ray, and Fermi-LAT γ-ray observations following the eruption for almost three years. V392 Per is one of the fastest evolving novae yet observed, with a t2 decline time of 2 days. Early spectra present evidence for multiple and interacting mass ejections, with the associated shocks driving both the γ-ray and early optical luminosity. V392 Per entered Sun-constraint within days of eruption. Upon exit, the nova had evolved to the nebular phase, and we saw the tail of the super-soft X-ray phase. Subsequent optical emission captured the fading ejecta alongside a persistent narrow line emission spectrum from the accretion disk. Ongoing hard X-ray emission is characteristic of a standing accretion shock in an intermediate polar. Analysis of the optical data reveals an orbital period of 3.230 ± 0.003 days, but we see no evidence for a white dwarf (WD) spin period. The optical and X-ray data suggest a high mass WD, the pre-nova spectral energy distribution (SED) indicates an evolved donor, and the post-nova SED points to a high mass accretion rate. Following eruption, the system has remained in a nova-like high mass transfer state, rather than returning to the pre-nova DN low mass transfer configuration. We suggest that this high state is driven by irradiation of the donor by the nova eruption. In many ways, V392 Per shows similarity to the well-studied nova and DN GK Persei

Current concept of abdominal sepsis : WSES position paper

Peer reviewe

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 1: The LBNF and DUNE Projects

This document presents the Conceptual Design Report (CDR) put forward by an international neutrino community to pursue the Deep Underground Neutrino Experiment at the Long-Baseline Neutrino Facility (LBNF/DUNE), a groundbreaking science experiment for long-baseline neutrino oscillation studies and for neutrino astrophysics and nucleon decay searches. The DUNE far detector will be a very large modular liquid argon time-projection chamber (LArTPC) located deep underground, coupled to the LBNF multi-megawatt wide-band neutrino beam. DUNE will also have a high-resolution and high-precision near detector