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Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR dim mice, in which absent GR dimerization leads to impaired GR–DNA-binding-dependent mechanisms but intact GR protein–protein interactions, were administered low-dose lipopolysaccharide (LPS). GR dim -LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-α (TNFα)), enhanced early expression of brain TNFα, IL-1β and IL-6 mRNA levels, and impaired later central TNFα mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR dim -LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFα expression. GR dim -LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization-dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low-dose endotoxin. Moreover, these results support the concept that GR protein–protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state.

We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model. This repression is noncompetitive and does not affect ligand binding or DNA binding, suggesting that anthrax lethal toxin (LeTx) probably exerts its effects through a cofactor(s) involved in the interaction between GR and the basal transcription machinery. LeTx-nuclear receptor repression is selective, repressing GR, progesterone receptor B (PR-B), and estrogen receptor α (ERα), but not the mineralocorticoid receptor (MR) or ERβ. GR repression was also caused by selected p38 mitogen-activated protein (MAP) kinase inhibitors, suggesting that the LeTx action may result in part from its known inactivation of MAP kinases. Simultaneous loss of GR and other nuclear receptor activities could render an animal more susceptible to lethal or toxic effects of anthrax infection by removing the normally protective antiinflammatory effects of these hormones, similar to the increased mortality seen in animals exposed to both GR antagonists and infectious agents or bacterial products. These finding have implications for development of new treatments and prevention of the toxic effects of anthrax.

Angiotensin II (Ang II) AT(1) receptors are involved in the regulation of the stress response. In adult male rats, acute restraint increased AT(1A) mRNA in paraventricular nucleus. Repeated restraint increased AT(1A) mRNA and AT(1) binding in paraventricular nucleus and AT(1) binding in subfornical organ and median eminence. AT(1B) and AT(2) receptors were not expressed in brain areas involved in the stress response. Acute restraint increased anterior pituitary AT(1A) mRNA and AT(1) binding and decreased AT(1B) mRNA. During repeated restraint, the increase in AT(1A) mRNA in the anterior pituitary was maintained, but AT(1B) mRNA and AT(1) binding returned to normal levels. In adrenal zona glomerulosa, AT(1B) mRNA, AT(1) binding, AT(2) mRNA and AT(2) binding decreased during acute restraint. Receptor mRNA and binding returned to normal after repeated stress, with the exception of rebound increase in adrenal zona glomerulosa AT(2) mRNA. In adrenal medulla, AT(1A) mRNA increased and AT(2) mRNA decreased during acute restraint. AT(1A) mRNA remained increased during repeated restraint, while alterations in AT(2) mRNA were no longer present. Expression of AT(1A), AT(1B) and AT(2) receptors in the hypothalamic-pituitary-adrenal axis is tissue specific and is different in acute and repeated stress. Increased brain, pituitary and adrenomedullary AT(1A) receptor expression correlates with hypothalamic-pituitary-adrenal axis stimulation, supporting the hypothesis of Ang II, through selective AT(1A) receptor stimulation, as an important determinant of the acute and repeated stress response. Decreased adrenal zona glomerulosa and anterior pituitary AT(1B) receptors during acute stress can be interpreted as compensatory to increased stimulation by Ang II. There may be additional roles for adrenal AT(2) receptors during acute stress, possibly related to interaction or cross-talk with AT(1) receptors.

Angiotensin II (Ang II) AT sub(1) receptors are involved in the regulation of the stress response. In adult male rats, acute restraint increased AT sub(1A) mRNA in paraventricular nucleus. Repeated restraint increased AT sub(1A) mRNA and AT sub(1) binding in paraventricular nucleus and AT sub(1) binding in subfornical organ and median eminence. AT sub(1B) and AT sub(2) receptors were not expressed in brain areas involved in the stress response. Acute restraint increased anterior pituitary AT sub(1A) mRNA and AT sub(1) binding and decreased AT sub(1B) mRNA. During repeated restraint, the increase in AT sub(1A) mRNA in the anterior pituitary was maintained, but AT sub(1B) mRNA and AT sub(1) binding returned to normal levels. In adrenal zona glomerulosa, AT sub(1B) mRNA, AT sub(1) binding, AT sub(2) mRNA and AT sub(2) binding decreased during acute restraint. Receptor mRNA and binding returned to normal after repeated stress, with the exception of rebound increase in adrenal zona glomerulosa AT sub(2) mRNA. In adrenal medulla, AT sub(1A) mRNA increased and AT sub(2) mRNA decreased during acute restraint. AT sub(1A) mRNA remained increased during repeated restraint, while alterations in AT sub(2) mRNA were no longer present. Expression of AT sub(1A), AT sub(1B) and AT sub(2) receptors in the hypothalamic-pituitary-adrenal axis is tissue specific and is different in acute and repeated stress. Increased brain, pituitary and adrenomedullary AT sub(1A) receptor expression correlates with hypothalamic-pituitary-adrenal axis stimulation, supporting the hypothesis of Ang II, through selective AT sub(1A) receptor stimulation, as an important determinant of the acute and repeated stress response. Decreased adrenal zona glomerulosa and anterior pituitary AT sub(1B) receptors during acute stress can be interpreted as compensatory to increased stimulation by Ang II. There may be additional roles for adrenal AT sub(2) receptors during acute stress, possibly related to interaction or cross-talk with AT sub(1) receptors.

The neurodevelopmental defects associated with ZIKV infections early in pregnancy are well documented, however the potential defects and long-term consequences associated with milder infections in late pregnancy and perinatal period are less well understood. To model these, we challenged 1 day old (P1) immunocompetent C57BL/6 mice with ZIKV. The animals developed a transient neurological syndrome including unsteady gait, kinetic tremors, severe ataxia and seizures 10–15 days post-infection (dpi) but symptoms subsided after a week, and most animals survived. Despite apparent recovery, MRI of convalescent mice show reduced cerebellar volume that correlates with altered coordination and motor function as well as hyperactivity and impulsivity. Persistent mRNA levels of pro-inflammatory genes including Cd80 , Il-1α , and Ifn-γ together with Cd3 , Cd8 and perforin ( PrfA) , suggested persistence of low-grade inflammation. Surprisingly, the brain parenchyma of convalescent mice harbor multiple small discrete foci with viral antigen, active apoptotic processes in neurons, and cellular infiltrates, surrounded by activated astrocytes and microglia as late as 1-year post-infection. Detection of negative-sense strand viral RNA and isolation of infectious virus derived from these convalescent mice by blinded passage in Vero cells confirmed long-term persistence of replicating ZIKV in CNS of convalescent mice. Although the infection appears to persist in defined reservoirs within CNS, the resulting inflammation could increase the risk of neurodegenerative disorders. This raises concern regarding possible long-term effects in asymptomatic children exposed to the virus and suggests that long-term neurological and behavioral monitoring as well as anti-viral treatment to clear virus from the CNS may be useful in patients exposed to ZIKV at an early age.

A new definition and classification of chronic kidney disease–mineral and bone disorder (CKD-MBD) was proposed in 2005 and it was later followed by a guideline publication on this topic from Kidney Disease: Improving Global Outcomes (KDIGO) in 2009. This work recognized that CKD-MBD is a syndrome of bone abnormalities, laboratory abnormalities, and vascular calcification linked to fractures, cardiovascular disease, and mortality. Because of limited data at the time of the original guideline systematic review, many of the recommendations were cautiously vague. KDIGO convened a Controversies Conference in October 2013 to review the CKD-MBD literature published since the 2009 guideline. Specifically, the objective of this conference was to determine whether sufficient new data had emerged to support a reassessment of the CKD-MBD guideline and if so to determine the scope of these potential revisions. This report summarizes the results of these proceedings, highlighting important new studies conducted in the interval since the original KDIGO CKD-MBD guideline.

Malignant breast tissue contains a rare population of multi-potent cells with the capacity to self-renew; these cells are known as cancer stem-like cells (CSCs) or tumor-initiating cells. Primitive mammary CSCs/progenitor cells can be propagated in culture as floating spherical colonies termed ‘mammospheres’. We show here that the expression of the autophagy protein Beclin 1 is higher in mammospheres established from human breast cancers or breast cancer cell lines (MCF-7 and BT474) than in the parental adherent cells. As a result, autophagic flux is more robust in mammospheres. We observed that basal and starvation-induced autophagy flux is also higher in aldehyde dehydrogenase 1-positive (ALDH1 + ) population derived from mammospheres than in the bulk population. Beclin 1 is critical for CSC maintenance and tumor development in nude mice, whereas its expression limits the development of tumors not enriched with breast CSCs/progenitor cells. We found that decreased survival in autophagy-deficient cells (MCF-7 Atg7 knockdown cells) during detachment does not contribute to an ultimate deficiency in mammosphere formation. This study demonstrates that a prosurvival autophagic pathway is critical for CSC maintenance, and that Beclin 1 plays a dual role in tumor development.

A decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain.

Intestinal and free-living protozoa, such as Giardia lamblia , express a dense coat of variant-specific surface proteins (VSPs) on trophozoites that protects the parasite inside the host’s intestine. Here we show that VSPs not only are resistant to proteolytic digestion and extreme pH and temperatures but also stimulate host innate immune responses in a TLR-4 dependent manner. We show that these properties can be exploited to both protect and adjuvant vaccine antigens for oral administration. Chimeric Virus-like Particles (VLPs) decorated with VSPs and expressing model surface antigens, such as influenza virus hemagglutinin (HA) and neuraminidase (NA), are protected from degradation and activate antigen presenting cells in vitro. Orally administered VSP-pseudotyped VLPs, but not plain VLPs, generate robust immune responses that protect mice from influenza infection and HA-expressing tumors. This versatile vaccine platform has the attributes to meet the ultimate challenge of generating safe, stable and efficient oral vaccines. Giardia lamblia express a dense coat of variant-specific surface proteins (VSPs) on trophozoites that protects the parasite inside the host´s intestine. Here the authors show that stability and immunomodulatory properties of VSPs can be exploited to both protect and adjuvant vaccine antigens for oral administration.