Modular and coordinated expression of immune system regulatory and signaling components in the developing and adult nervous system.

During development, the nervous system (NS) is assembled and sculpted through a concerted series of neurodevelopmental events orchestrated by a complex genetic programme. While neural-specific gene expression plays a critical part in this process, in recent years, a number of immune-related signaling and regulatory components have also been shown to play key physiological roles in the developing and adult NS. While the involvement of individual immune-related signaling components in neural functions may reflect their ubiquitous character, it may also reflect a much wider, as yet undescribed, genetic network of immune-related molecules acting as an intrinsic component of the neural-specific regulatory machinery that ultimately shapes the NS.

Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood.

Early-life adverse experiences, including prenatal stress (PNS), are associated with a higher prevalence of neurodevelopmental, cardiovascular and metabolic disorders in affected offspring. Here, in a rat model of chronic PNS, we investigate the impact of late gestational stress on physiological outcomes in adulthood. Sprague-Dawley pregnant dams were subjected to repeated restraint stress from embryonic day 14 to day 20, and their male offspring were assessed at 4 months of age.

Immunoglobulin E plays an immunoregulatory role in lupus.

The (patho)physiological role of IgE in nonallergic inflammatory diseases is not well understood. Here, we explored the effect of IgE deficiency on the inflammatory response in FcγRIIB-deficient mice as well as in mice carrying both a deletion of FcγRIIB and the chromosomal translocation of Y-linked autoimmune acceleration (Yaa) that hastens and results in a more aggressive lupuslike disease in these mice. The findings show that deficiency of IgE delays disease development and severity as demonstrated by reduced autoantibody production and amelioration of organ pathologies.

Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics.

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality.

Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive.

Spontaneous activation of RNA-sensing pathways in autoimmune disease.

Multiple intracellular RNA sensing innate immune pathways have been linked to autoimmune disease. RNA-related ligands taken up by the endocytic pathway activate TLRs, and affect primarily immune cells. This type of activation is enhanced by nucleic acid-specific antibodies and induces an inflammatory program.

NF-κB: emerging roles in hippocampal development and function.

The nuclear factor kappa-B family of transcription factors have been extensively studied in the immune system where they function to orchestrate the molecular response to immune challenge. However in recent years, members of this family have also been shown to play physiological roles in the development and function of the nervous system. The two best studied members of the nuclear factor kappa-B family are the p65 and the p50 proteins.

The intracellular portion of GITR enhances NGF-promoted neurite growth through an inverse modulation of Erk and NF-κB signalling.

NF-κB transcription factors play a key role in regulating the growth of neural processes in the developing PNS. Although several secreted proteins have been shown to activate NF-κB to inhibit the growth of developing sympathetic neurons, it is unknown how the endogenous level of NF-κB activity present in these neurons is restricted to allow neurite growth to occur during their normal development. Here we show that activation of the glucocorticoid-induced tumour necrosis factor receptor (GITR) inhibits NF-κB activation while promoting the activation of Erk in developing sympathetic neurons.

Cation exchange surface-mediated denaturation of an aglycosylated immunoglobulin (IgG1).

Cation exchange chromatography of an aglycosylated IgG1 resulted in two distinct peaks during gradient elution. The early eluting peak contained <1% high molecular weight (HMW) species, while the later peak contained 23% HMW species. Analysis by hydrogen-deuterium exchange and Fourier transform infrared spectroscopy (FTIR) indicated that aggregate formation and generation of the second peak were caused by antibody denaturation on the resin surface.

Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity.

Type I IFNs (IFN-I) are normally produced during antiviral responses, yet high levels of chronic IFN-I expression correlate with autoimmune disease. A variety of viral sensors generate IFN-I in their response, but other than TLRs, it is not fully known which pathways are directly involved in the development of spontaneous immune pathologies. To further explore the link between IFN-I induced by viral pathways and autoimmunity, we generated a new transgenic mouse line containing multiple copies of Ifih1, a gene encoding the cytoplasmic dsRNA sensor MDA5 with proven linkage to diabetes and lupus.

Exposure of foetal neural progenitor cells to IL-1β impairs their proliferation and alters their differentiation - a role for maternal inflammation?

During pregnancy, activation of the maternal immune system results in inflammation in the foetal nervous system. The causative agents are pro-inflammatory cytokines like interleukin-1β (IL-1β), produced by the foetus. In this study, we examine the effect of IL-1β on the proliferation and differentiation of neural progenitor cells (NPCs) to better understand its potential effects on the developing brain.

Innate pathways to B-cell activation and tolerance.

B cells represent an important link between the adaptive and innate immune systems as they express both antigen-specific B-cell receptors (BCRs) as well as various Toll-like receptors (TLRs). Several checkpoints in B-cell development ensure that self-specific cells are eliminated from the mature B-cell repertoire to avoid harmful autoreactive responses. These checkpoints are controlled by BCR-mediated events but are also influenced by TLR-dependent signals from the innate immune system.

Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2.

Background: THE COMPLEXITY OF WNT SIGNALING LIKELY STEMS FROM TWO SOURCES: multiple pathways emanating from frizzled receptors in response to wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals downstream of growth factor and matrix receptors. Both rac1 and c-jun have recently been implicated in wnt signaling, however their upstream activators have not been identified.

Methodology/principal Findings: Here we identify the adapter protein Grb2, which is itself an integrator of multiple signaling pathways, as a modifier of beta-catenin-dependent wnt signaling.

Isolation of human umbilical vein endothelial cells (HUVEC).

Angiogenesis is a complex multi-step process, where in response to angiogenic stimuli, new vessels are created from the existing vasculature. These steps include: degradation of the basement membrane, proliferation and migration (sprouting) of endothelial cells (EC) into the extracellular matrix, alignment of EC into cords, lumen formation, anastomosis, and formation of a new basement membrane. Many in vitro assays have been developed to study this process, but most only mimic certain stages of angiogenesis, and morphologically the vessels often do not resemble vessels in vivo.

Anion binding mediated precipitation of a peptibody.

Purpose: Understand the underlying mechanism governing the salt-induced precipitation of a basic (pI = 8.8) protein, Peptibody A (PbA), in acidic solutions.

Methods: The rate, extent, and reversibility of PbA precipitation was monitored over 4-weeks as a function of pH (3.

Employees' need for speed: methamphetamine in the workplace.

Methamphetamine is a profoundly addictive drug that seriously impacts health, families, businesses, social services, and the environment. The nature of these hazards makes it prudent for every organization to update its current policies and emergency action plans. We recommend training employees to identify and react appropriately to the wide range of methamphetamine hazards as a means of improving the management of other workplace hazards and emergencies.

Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration.

Wnts are a family of secreted glycoproteins with diverse developmental roles, including regulation of cell migration; however, little is known about wnt signaling in mature T cells. We find that endothelial-cell-derived wnts, acting through Frizzled receptors, induce matrix metalloproteinase (MMP) 2 and MMP9 expression in effector T cells. Blocking wnt signaling, or MMP activity, reduces T cell migration through the basement membrane in vitro and into inflamed skin in vivo.

Matrix metalloproteinase-7 activation of mouse paneth cell pro-alpha-defensins: SER43 down arrow ILE44 proteolysis enables membrane-disruptive activity.

Small intestinal Paneth cells secrete alpha-defensin microbicidal peptides as mediators of innate enteric immunity. In mice, production of mature Paneth cell alpha-defensins, termed cryptdins (Crps), requires proteolytic activation of inactive precursors (pro-Crps) by the convertase matrix metalloproteinase-7. Proteolysis of mouse (pro-Crp4)(20-92) produces the specific cleavage intermediates pro-Crp4(44-92), pro-Crp4(54-92), and pro-Crp4(59-92).

Assessing the standard of care for child and adolescent attention-deficit hyperactivity disorder in Elgin County, Ontario: a pilot study.

Objective: To examine the current practice of rural family physicians in managing children with attention-deficit hyperactivity disorder (ADHD).

Design: Chart review of children and adolescents with a recorded diagnosis of ADHD. The data collected include the patient's age at diagnosis, the diagnosing physician, the number and type of presenting symptoms, whether the Diagnostic Statistical Manual, 4th ed (DSM-IV) criteria were met, pertinent treatment regimens, family history and comorbid conditions.

Endothelial cell co-stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA.

Human endothelial cells (ECs) constitutively express OX40L and co-stimulate memory CD4(+) T cell proliferation that is dependent upon OX40-OX40L interaction. In vivo, OX40 prolongs T cell survival; however, an unanswered question is whether it can also prolong synthesis of proliferation-sustaining cytokines such as IL-2. Here we show that EC co-stimulation results in the secretion of T cell IL-2, IL-3 and IFN-gamma and that in the absence of OX40 signals synthesis largely ceases by 12-18 h, but is prolonged up to 60 h in the presence of OX40 signaling.

Head-up tilting is a useful provocative test for psychogenic non-epileptic seizures.

Differentiating psychogenic non-epileptic attack disorder (NEAD) from true epilepsy is difficult. This often results in a misdiagnosis and unnecessary and ineffective treatment. Prolonged EEG/video recording is the most sensitive tool for differentiating NEAD from epilepsy, but is costly and therefore limited in availability.

Proinflammatory cytokine and human immunodeficiency virus RNA levels during early Mycobacterium avium complex bacteremia in advanced AIDS.

The relationship between Mycobacterium avium complex (MAC) bacteremia and proinflammatory cytokine and human immunodeficiency virus type 1 (HIV-1) RNA levels in AIDS was investigated. During a prospective study, blood samples were drawn monthly for mycobacterial cultures. Sera were available at baseline and onset of MAC bacteremia from 20 cases and at corresponding times from 19 controls.