Measuring allostatic load in an urban adolescent sample: The profile and role of biomarker dysregulation in depression outcomes

Accumulated, chronic stress exposure is well established as a precursor for allostatic load (AL). Both stress exposure and AL have been associated with depression in the existing literature. While many studies have focused on biomarkers representative of various physiological systems, a clear understanding of how physiological AL results in depression is yet unclear. Further, variability of hypo- and hypercortisolemic profiles have been associated with depression. A review of the existing literature supports hypocortisolemic profiles in relation to female depression and hypercortisolemic profiles in male depression across both adolescent and adult populations. The function of alpha-amylase (AA) dysregulation within the context of depression is even less well established. Previous research (Ali & Pruessner, 2012) has suggested a ratio of AA area under the curve with respect to ground (AUCg) over cortisol (CORT) AUCg, termed AOCg, as an indicator of the asymmetry between CORT and AA, and therefore, the hypothalamic pituitary adrenal (HPA) axis and sympathetic nervous system (SNS). Research supports an imbalance between these two systems may be representative of AL. AOCg has been correlated with major event exposure and depression in an adult sample. Adolescence is a sensitive biological period, perhaps posing even greater risk for the development of depressive symptoms within the context of AL. This provides rationale for use of the AOCg metric in an adolescent sample. A review of theory on stress research by Grant and colleagues (2003) posits a model for the etiology of psychopathology from stress exposure through the examination of potential biological mediators and moderators. The current study sought to further existing information on stress accumulation, AL, and depression by testing a path model with AUCg and area under the curve with respect to increase (AUCi) metrics of AA and CORT as mediators of the relationship between major events (ME), daily hassles (DH), and violent crime exposure (VC) with self-reported depression symptoms at two time points. We hypothesized that increased AUCg/AUCi of both CORT and AA would mediate the relationship between stressors and depression symptoms. We also hypothesized biological sex and parent depression severity would moderate the relationship between the physiological stress response and depression symptoms. In addition, the current study sought to replicate findings from the Ali & Pruessner study in an adolescent sample by running multiple regression analyses to identify associations between AOCg, stress, and depression symptoms. Results of the analyses indicate AUCg/AUCi metrics of AA and CORT do not mediate the relationship between stressors and depression symptoms. Regarding sex differences, female adolescents in the current sample exhibited a blunted response to the acute stressor task compared with males and presented with significantly more depression symptoms. AOCg was not significantly associated with depression symptoms in our adolescent sample but was significantly and positively associated with VC. Follow-up analyses indicate more VC is associated with lower COAg and that more COAg predicts less depression in adolescents. In addition, the use of more disengagement coping (DC) in response to more DH led to more depression symptoms at time one and lower AUCg AA values. Greater AUCg AA values in the current study were associated with less depression symptoms at time one and greater depression symptoms at time two. These results parallel previous studies demonstrating more SNS reactivity over time with failure to habituate contributes to changes in neurobiological processes that create vulnerability for increased depression symptoms (McCarty, 2016). The current study provided further support for the need to utilize multiple measures of the stress response to elucidate associations between specific stressor types and specific parts of the stress response system that may be most impacted. In addition, the current study added to the topic of AA measurement in adolescents by identifying an association between AA with a chronic, uncontrollable distal stressor (VC) and identifying a positive association between AA and depression symptoms over time in a community sample of adolescent

Beyond panic: navigating the tides of change in relationships and sex education

This paper critically evaluates societal reactions to integrating LGBTQ+ content into the Relationship and Sex Education (RSE) curriculum in England and Wales. Utilising Stanley Cohen’s theory of moral panics, it examines the roles of media, moral entrepreneurs, authorities, and the public in shaping debates around educational reforms. The paper highlights the complexities of balancing traditional values and inclusivity in education, emphasising the necessity of a considerate and comprehensive RSE approach. The study employs mixed methods, combining qualitative and quantitative analyses, to explore the multifaceted nature of this societal issue and its wider implications

Sensitization of CD8 T Cells During Acute Viral Infections Impacts Bystander and Latecomer CD8 T Cell Responses : A Dissertation

Many virus infections induce a transient state of immune suppression in the infected host. Virus-induced T cell suppression can be caused by T cell activation-induced cell death (AICD), dendritic cell (DC) apoptosis, DC dysfunction, and/or the enhanced expression of immune-suppressive cytokines. It has been previously demonstrated that naïve bystander CD8 T cells derived from hosts experiencing an acute virus-specific T cell response underwent AICD when polyclonally activated by anti-CD3 in vitro (Zarozinski et al., 2000). Susceptibility of naïve bystander T cells to AICD could prevent the development of a new T cell response during an ongoing immune response, and thus render infected hosts immune suppressed. Although immune suppression could result in an enhanced susceptibility to superinfections, virus-infected individuals are more commonly resistant to superinfecting pathogens. Because of these seemingly contradictory conditions, we sought to investigate how acute viral infections impact naïve bystander CD8 T cells in vivo. More specifically, we asked whether bystander CD8 T cells are susceptible to immune suppression or whether they can contribute to the resistance to superinfections. In order to address this, we examined the responses of bystander CD8 T cells activated with cognate antigen during acute viral infections in vivo. We generated several in vivomodels using P14 (LCMV glycoprotein-specific), HY (male antigen-specific), and OT-I (ovalbumin-specific) transgenic CD8 T cells, which we defined as bystander during acute infections with lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PV), vaccinia virus (VV), and murine cytomegalovirus (MCMV). Consistent with the enhanced susceptibility to cell death noted in vitro, we found that bystander CD8 T cells activated with cognate antigen in vivo during acute viral infections underwent markedly reduced proliferation. Virus-induced transient T cell suppression in vivo was not exclusively mediated by Fas-FasL- or TNF-induced AICD or due to an enhanced susceptibility to apoptosis. Instead, immune suppression in vivowas associated with a delayed onset of division, which we found not to be due to a defect in antigen presentation, but rather due to a T cell intrinsic defect. Despite the suppressed proliferation of TCR-stimulated bystander CD8 T cells in vivo, we found an enhancement of the effector functions exerted by bystander CD8 T cells activated during acute viral infections. During acute viral infections or after stimulation with type 1 IFN (IFN-αβ) inducers, some bystander CD8 T cells were sensitized to immediately exert effector functions such as IFN-γ production and degranulation upon stimulation with high affinity cognate antigen. Sensitization of naïve CD8 T cells required self-MHC I and indirect effects of IFN-αβ, while IL-12, IL-18, and IFN-γ were not individually required. IL-15 was not required for the rapid expression of IFN-γ, but was required for up-regulation of granzyme B (GrzB). P14 and OT-I CD8 T cells, which are capable of homeostatic proliferation, could be sensitized by poly(I:C), but HY CD8 T cells, which are poor at homeostatic proliferation, could not, suggesting that the requirement for MHC I may be to present low affinity cryptically cross-reactive self antigens. Sensitized naive CD8 T cells up-regulated the t-box transcription factor Eomesodermin (Eomes), which can regulate these rapid effector functions. In conclusion, we demonstrate in this thesis that acute viral infections impact naïve bystander CD8 T cells such that their response to cognate antigen is altered. Prior to cognate antigen engagement, bystander CD8 T cells up-regulated Eomes, CD122, and GrzB. Following cognate antigen engagement, bystander CD8 T cells rapidly degranulated and expressed the effector cytokine IFN-γ. The ability of bystander CD8 T cells to rapidly exert effector functions may contribute to the resistance of virus-infected individuals to superinfections. Despite these rapid effector functions, the proliferation of TCR-stimulated bystander CD8 T cells was markedly inhibited. This reduced proliferation was found not to be a defect in antigen presentation, but was a T cell intrinsic defect in initiating division. Thus, bystander CD8 T cells were also susceptible to virus-induced immune suppression. It is also likely that virus-specific CD8 T cells that are not activated until later in the response, so-called latecomer CD8 T cells, may also be susceptible to immune enhancement and suppression. Thus, latecomer CD8 T cells would be able to rapidly exert effector functions at the expense of proliferation. Taken together, we propose that during an immune response, due to spatial and temporal gradients of antigen and inflammation, it is likely that a combination of heterogeneous T cells with different signal strengths and sequences of exposure from cytokines and peptide-MHC constitute the total T cell response to pathogens

On the Nonexistence of Singular Equilibria in the Four-vortex Problem

In this paper we provide a partial answer to a question recently posed by Hassan Aref et. al. in their article Vortex Crystals, namely whether there are certain singular equilibria of point vortices. We prove that there are no such equilibria in the four-vortex case

Early head injury and attention deficit hyperactivity disorder: retrospective cohort study

Objective To explore the hypothesis that medically attended head injury in young children may be causal in the later development of attention deficit hyperactivity disorder

Type 1 Interferons and Antiviral CD8 T-Cell Responses

Type 1 interferons (IFNs) were the first cytokines discovered and include IFNβ, more than ten forms of IFNα, and several other related molecules that all bind to the same type 1 IFN receptor (IFN1R). Type 1 IFNs are commonly referred to as “viral” IFNs because they can be induced directly by virus infections, in contrast to “immune” IFN, or IFNγ, which is synthesized after receptor engagement of T cells and natural killer (NK) cells during immune responses. Type 1 IFNs get induced by viral nucleic acids and proteins acting on cellular signaling molecules such as Toll-like receptors and RNA helicases, which, in turn, release transcription factors into the nucleus. Mice lacking IFN1R appear normal in a pathogen-free environment but are extraordinarily susceptible to virus infections. This susceptibility is partially due to IFN-regulated genes that suppress viral replication, but type 1 IFNs also have many immunoregulatory properties that could also affect host susceptibility to infection

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10\u2009m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that \u3b1-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that \u3b1-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients