Neuropsychological Functioning in Sexual Offenders With and Without Pedophilic Disorder.

This study sought to examine neuropsychological functioning in men with pedophilic disorder (PD), in order to assess whether findings from prior neuropsychological studies are replicated in a diverse sample including men with non-contact sexual offenses. It was hypothesized that when non-contact offenders are included in the study, a slowed processing speed will emerge as the only finding unique to men with PD. A comprehensive neuropsychological battery was administered to 58 men convicted of a sexual offense, 20 of whom were classified as having PD. The sample included men with contact sexual offenses (n = 33), non-contact sexual offenses (n = 5), and child sexual abuse material (CSAM) offenses (n = 20). Test performance was compared by PD status. Participants with PD performed significantly better on verbal memory and visual discrimination than those without PD. Men with PD made more errors on a set-shifting task but no significant differences were seen in domains of attention, intellectual functioning, visual learning and memory, visuospatial ability, or language ability. Effect sizes were generally small, although some medium effects were seen (visual discrimination and verbal learning and memory). Scores in both groups (with and without PD) were generally in the average range across tasks. Within the subgroup of CSAM offenders, minimal differences emerged between those with and without PD, although those with PD were slower on visuomotor set-shifting but made fewer errors (d = - 0.89). CSAM offenders with PD were in the high average range on many tasks of intellectual functioning; however, a potential trend was identified such that CSAM offenders without PD had lower scores on a task of verbal learning and memory, with medium effect sizes observed. As few differences in neuropsychological functioning emerged when comparing offenders with and without PD, differences demonstrated in prior research may be better attributed to contact offending status rather than sexual interest.

In Vitro and In Vivo Safety of Hyaluronic Acid-Decorated Microparticles for Intravitreal Injection of Palmitoylethanolamide, Citicoline, or Glial-Cell-Derived Neurotrophic Factor.

The treatment of posterior eye segment diseases through intravitreal injection requires repeated injections of an active molecule, which may be associated with serious side effects and poor patient compliance. One brilliant strategy to overcome these issues is the use of drug-loaded microparticles for sustained release, aiming at reducing the frequency of injections. Therefore, the aim of this work was to assess the safety features of poly(lactic-co-glycolic acid) (PLGA)-based, hyaluronic acid-decorated microparticles loaded with palmitoylethanolamide (PEA), citicoline (CIT), or glial-cell-derived neurotrophic factor (GDNF). Microparticles were prepared by double emulsion-solvent evaporation and fully characterized for their technological features. Microparticles possessed a satisfactory safety profile in vitro on human retinal pigment epithelial (ARPE-19) cells. Interestingly, the administration of free GDNF led to a loss of cell viability, while GDNF sustained release displayed a positive effect in that regard. In vivo results confirmed the safety profile of both empty and loaded microparticles. Overall, the outcomes suggest that the produced microparticles are promising for improving the local administration of neuroprotective molecules. Further studies will be devoted to assess the therapeutic ability of microparticles.

Markers of systemic inflammation are positively associated with influenza vaccine antibody responses with a possible role for ILT2(+)CD57(+) NK-cells.

BACKGROUND: With increasing age, overall health declines while systemic levels of inflammatory mediators tend to increase. Although the underlying mechanisms are poorly understood, there is a wealth of data suggesting that this so-called "inflammaging" contributes to the risk of adverse outcomes in older adults. We sought to determine whether markers of systemic inflammation were associated with antibody responses to the seasonal influenza vaccine. RESULTS: Over four seasons, hemagglutination inhibition antibody titres and ex vivo bulk peripheral blood mononuclear cell (PBMC) responses to live influenza viruses assessed via interferon (IFN)-γ/interleukin (IL)-10 production, were measured pre- and 4-weeks post-vaccination in young adults (n = 79) and older adults randomized to standard- or high-dose inactivated vaccine (n = 612). Circulating tumour necrosis factor (TNF), interleukin (IL)-6 and C-reactive protein (CRP) were also measured pre-vaccination. Post-vaccination antibody titres were significantly associated with systemic inflammatory levels; specifically, IL-6 was positively associated with A/H3N2 titres in young adults (Cohen's d = 0.36), and in older high-dose, but not standard-dose recipients, all systemic inflammatory mediators were positively associated with A/H1N1, A/H3N2 and B titres (d = 0.10-0.45). We further show that the frequency of ILT2(+)CD57(+) CD56-Dim natural killer (NK)-cells was positively associated with both plasma IL-6 and post-vaccination A/H3N2 titres in a follow-up cohort of older high-dose recipients (n = 63). Pathway analysis suggested that ILT2(+)CD57(+) Dim NK-cells mediated 40% of the association between IL-6 and A/H3N2 titres, which may be related to underlying participant frailty. CONCLUSIONS: In summary, our data suggest a complex relationship amongst influenza vaccine responses, systemic inflammation and NK-cell phenotype in older adults, which depends heavily on age, vaccine dose and possibly overall health status. While our results suggest that "inflammaging" may increase vaccine immunogenicity in older adults, it is yet to be determined whether this enhancement contributes to improved protection against influenza disease.

Neuroprotective Effects of Transferrin in Experimental Glaucoma Models.

Iron is essential for retinal metabolism, but an excess of ferrous iron causes oxidative stress. In glaucomatous eyes, retinal ganglion cell (RGC) death has been associated with dysregulation of iron homeostasis. Transferrin (TF) is an endogenous iron transporter that controls ocular iron levels. Intraocular administration of TF is neuroprotective in various models of retinal degeneration, preventing iron overload and reducing iron-induced oxidative stress. Herein, we assessed the protective effects of TF on RGC survival, using ex vivo rat retinal explants exposed to iron, NMDA-induced excitotoxicity, or CoCl2-induced hypoxia, and an in vivo rat model of ocular hypertension (OHT). TF significantly preserved RGCs against FeSO4-induced toxicity, NMDA-induced excitotoxicity, and CoCl2-induced hypoxia. TF protected RGCs from apoptosis, ferroptosis, and necrosis. In OHT rats, TF reduced RGC loss by about 70% compared to vehicle-treated animals and preserved about 47% of the axons. Finally, increased iron staining was shown in the retina of a glaucoma patient's eye as compared to non-glaucomatous eyes. These results indicate that TF can interfere with different cell-death mechanisms involved in glaucoma pathogenesis and demonstrate the ability of TF to protect RGCs exposed to elevated IOP. Altogether, these results suggest that TF is a promising treatment against glaucoma neuropathy.

MDSCs, ageing and inflammageing.

The challenge of distinguishing between changes attributable to ageing and those attributable to pathology is even greater for the immune system than for many other organs, and this is especially true for myeloid-derived suppressor cells (MDSCs). Hematopoiesis is different in older adults with a bias towards myelopoiesis, and older adults also manifest "inflammageing" exacerbated by disease and contributing to MDSC induction. Hence, at least in humans, one can only investigate MDSCs in the context of ageing and disease states, and not in the context of ageing processes per se. This contribution provides a brief overview of the literature on MDSCs and ageing in humans.

Weibel-Palade Bodies Orchestrate Pericytes During Angiogenesis.

Objective Weibel-Palade bodies (WPBs) are endothelial cell (EC)-specific organelles formed by vWF (von Willebrand factor) polymerization and that contain the proangiogenic factor Ang-2 (angiopoietin-2). WPB exocytosis has been shown to be implicated for vascular repair and inflammatory responses. Here, we investigate the role of WPBs during angiogenesis and vessel stabilization. Approach and Results WPB density in ECs decreased at the angiogenic front of retinal vascular network during development and neovascularization compared with stable vessels. In vitro, VEGF (vascular endothelial growth factor) induced a VEGFR-2 (vascular endothelial growth factor receptor-2)-dependent exocytosis of WPBs that contain Ang-2 and consequently the secretion of vWF and Ang-2. Blocking VEGF-dependant WPB exocytosis and Ang-2 secretion promoted pericyte migration toward ECs. Pericyte migration was inhibited by adding recombinant Ang-2 or by silencing Ang-1 (angiopoietin-1) or Tie2 (angiopoietin-1 receptor) in pericytes. Consistently, in vivo anti-VEGF treatment induced accumulation of WPBs in retinal vessels because of the inhibition of WPB exocytosis and promoted the increase of pericyte coverage of retinal vessels during angiogenesis. In tumor angiogenesis, depletion of WPBs in vWF knockout tumor-bearing mice promoted an increase of tumor angiogenesis and a decrease of pericyte coverage of tumor vessels. By another approach, normalized tumor vessels had higher WPB density. Conclusions We demonstrate that WPB exocytosis and Ang-2 secretion are regulated during angiogenesis to limit pericyte coverage of remodeling vessels by disrupting Ang-1/Tie2 autocrine signaling in pericytes.

Review: The bile acids urso- and tauroursodeoxycholic acid as neuroprotective therapies in retinal disease.

Bile acids are produced in the liver and excreted into the intestine, where their main function is to participate in lipid digestion. Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have shown antiapoptotic, anti-inflammatory, and antioxidant effects in various models of neurodegenerative diseases. However, little is known about signaling pathways and molecular mechanisms through which these bile acids act as neuroprotectors, delaying translation to the clinical setting. We review evidence supporting a potentially therapeutic role for bile acids in retinal disorders, and the mechanisms and pathways involved in the cytoprotective effects of bile acids from the liver and the enterohepatic circulation to the central nervous system and the retina. As secondary bile acids are generated by the microbiota metabolism, bile acids might be a link between neurodegenerative retinal diseases and microbiota.

Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells.

Telomerase is a prototype-shared tumor Ag and represents an attractive target for anticancer immunotherapy. We have previously described promiscuous and immunogenic HLA-DR-restricted peptides derived from human telomerase reverse transcriptase (hTERT) and referred as universal cancer peptide (UCP). In nonsmall cell lung cancer, the presence of spontaneous UCP-specific CD4 T cell responses increases the survival of chemotherapy-responding patients. However, the precise mechanisms of hTERT's uptake, processing, and presentation on MHC-II molecules to stimulate CD4 T cells are poorly understood. In this work, by using well-characterized UCP-specific CD4 T cell clones, we showed that hTERT processing and presentation on MHC-II involve both classical endolysosomal and nonclassical cytosolic pathways. Furthermore, to our knowledge, we demonstrated for the first time that hTERT's internalization by dendritic cells requires its interaction with surface heparan sulfate proteoglycans. Altogether, our findings provide a novel mechanism of tumor-specific CD4 T cell activation and will be useful for the development of novel cancer immunotherapies that harness CD4 T cells.

IL-21-Induced MHC Class II+ NK Cells Promote the Expansion of Human Uncommitted CD4+ Central Memory T Cells in a Macrophage Migration Inhibitory Factor-Dependent Manner.

NK cells are critical for innate immunity-mediated protection. The main roles of NK cells rely on their cytotoxic functions or depend on the tuning of Th1 adaptive immunity by IFN-γ. However, the precise influence of inflammatory cytokines on NK cell and CD4 T lymphocyte interactions was never investigated. In this study, we provide evidence that IL-21, a cytokine produced during chronic inflammation or infectious diseases, promotes the differentiation of a specific subset of NK cells coexpressing CD86 and HLA-DR and lacking NKp44. More importantly, IL-21-propagated HLA-DR(+) NK cells produce macrophage migration inhibitory factor and provide costimulatory signaling during naive CD4(+) T cell priming inducing the differentiation of uncommitted central memory T cells. Central memory T cells expanded in the presence of HLA-DR(+) NK cells are CXCR3(+)CCR6(-)CCR4(-)CXCR5(-) and produce IL-2, as well as low levels of TNF-α. Costimulation of CD4(+) T cells by HLA-DR(+) NK cells prevents the acquisition of effector memory phenotype induced by IL-2. Moreover, we identified this population of NK HLA-DR(+) macrophage migration inhibitory factor(+) cells in inflammatory human appendix. Collectively, these results demonstrate a novel function for IL-21 in tuning NK and CD4(+) T cell interactions promoting a specific expansion of central memory lymphocytes.

Retinal safety of intravitreal rtPA in healthy rats and under excitotoxic conditions.

PURPOSE: Intravitreal recombinant tissue plasminogen activator (rtPA) is used off-label for the surgical management of submacular hemorrhage, a severe complication of neovascular age-related macular degeneration. rtPA is approved for coronary and cerebral thrombolysis. However, in ischemic stroke rtPA is known to increase excitotoxic neural cell death by interacting with the N-methyl-D-aspartate (NMDA) receptor. We therefore investigated the retinal toxicity of rtPA in healthy rats and in a model of NMDA-induced retinal excitotoxicity. METHODS: First, rtPA at three different doses (2.16 µg/5 µl, 0.54 µg/5 µl, and 0.27 µg/5 µl) or vehicle (NaCl 0.9%) was injected intravitreally in healthy rat eyes. Electroretinograms (ERGs) were performed at 24 h or 7 days. Annexin V-fluorescein isothiocyanate (FITC)-labeled apoptotic retinal ganglion cells (RGCs) were counted on flatmounted retinas at 24 h or 7 days. Next, NMDA + vehicle or NMDA + rtPA (0.27 µg/5 µl) was injected intravitreally to generate excitotoxic conditions. Apoptotic annexin V-FITC-labeled RGCs and surviving Brn3a-labeled RGCs were quantified on flatmounted retinas and radial sections, 18 h after treatment. RESULTS: In healthy rat eyes, the number of apoptotic RGCs was statistically significantly increased 24 h after the administration of rtPA at the highest dose (2.16 µg/5 µl; p = 0.0250) but not at the lower doses of 0.54 and 0.27 µg/5 µl (p = 0.36 and p = 0.20), compared to vehicle. At day 7, there was no difference in the apoptotic RGC count between the rtPA- and vehicle-injected eyes (p = 0.70, p = 0.52, p = 0.11). ERG amplitudes and implicit times were not modified at 24 h or 7 days after injection of any tested rtPA doses, compared to the baseline. Intravitreal administration of NMDA induced RGC death, but under these excitotoxic conditions, coadministration of rtPA did not increase the number of dead RGCs (p = 0.70). Similarly, the number of surviving RGCs on the flatmounted retinas and retinal sections did not differ between the eyes injected with NMDA + vehicle and NMDA + rtPA (p = 0.59 and p = 0.67). CONCLUSIONS: At low clinical equivalent doses corresponding to 25 µg/0.1 ml in humans, intravitreal rtPA is not toxic for healthy rat retinas and does not enhance NMDA-induced excitotoxicity. Vitreal equivalent doses ≥200 µg/0.1 ml should be avoided in patients, due to potential RGC toxicity.

Posttraumatic Stress among Victimized Latino Women: Evaluating the Role of Cultural Factors.

Research examining victimization and posttraumatic symptomatology among Latinos is lacking in the extant literature. This analysis used the victimized subsample (N = 752) of the Sexual Assault Among Latinas Study. The aim was to evaluate victimization prevalence and test the following hypotheses: (a) that victimization would be associated with higher levels of posttraumatic symptoms, (b) that cultural factors that move away from traditional Latino culture would be associated with higher levels of posttraumatic symptomatology, and (c) that cultural factors associated with traditional Latino culture would be related to lower posttraumatic symptomatology. Average age of the sample was 44.57 years, with three fourths having a high school education or higher, and two thirds having a household income below $30,000. Of exposure types, adulthood threats were most likely to result in Criterion A traumatic events (23.4%). Using the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000) based PTSD Checklist, between 8.8% and 45.5% of individuals met presumed PTSD diagnosis based on various PCL cut scores or algorithm criteria. Regression analyses indicated that the combined different types of adult and childhood victimizations, masculine gender role, and negative religious coping were associated with increased symptoms (ßs ranging from .16 to .27). The results suggested a role of culture in posttraumatic symptoms for Latinas.

Phototoxicity of low doses of light and influence of the spectral composition on human RPE cells.

Light is known to induce retinal damage affecting photoreceptors and retinal pigment epithelium. For polychromatic light, the blue part of the spectrum is thought to be the only responsible for photochemical damage, leading to the establishment of a phototoxicity threshold for blue light (445 nm). For humans it corresponds to a retinal dose of 22 J/cm2. Recent studies on rodents and non-human primates suggested that this value is overestimated. In this study, we aim at investigating the relevance of the current phototoxicity threshold and at providing new hints on the role of the different components of the white light spectrum on phototoxicity. We use an in vitro model of human induced pluripotent stem cells (hiPSC)-derived retinal pigment epithelial (iRPE) cells and exposed them to white, blue and red lights from LED devices at doses below 22 J/cm2. We show that exposure to white light at a dose of 3.6 J/cm2 induces an alteration of the global cellular structure, DNA damage and an activation of cellular stress pathways. The exposure to blue light triggers DNA damage and the activation of autophagy, while exposure to red light modulates the inflammatory response and inhibits autophagy.

Glyburide confers neuroprotection against age-related macular degeneration (AMD).

Glyburide, a sulfonylurea drug used to treat type 2 diabetes, boasts neuroprotective effects by targeting the sulfonylurea receptor 1 (SUR1) and associated ion channels in various cell types, including those in the central nervous system and the retina. Previously, we demonstrated that glyburide therapy improved retinal function and structure in a rat model of diabetic retinopathy. In the present study, we explore the application of glyburide in non-neovascular ("dry") age-related macular degeneration (AMD), another progressive disease characterized by oxidative stress-induced damage and neuroinflammation that trigger cell death in the retina. We show that glyburide administration to a human cone cell line confers protection against oxidative stress, inflammasome activation, and apoptosis. To corroborate our in vitro results, we also conducted a case-control study, controlling for AMD risk factors and other diabetes medications. It showed that glyburide use in patients reduces the odds of new-onset dry AMD. A positive dose-response relationship is observed from this analysis, in which higher cumulative doses of glyburide further reduce the odds of new-onset dry AMD. In the quest for novel therapies for AMD, glyburide emerges as a promising repurposable drug given its known safety profile. The results from this study provide insights into the multifaceted actions of glyburide and its potential as a neuroprotective agent for retinal diseases; however, further preclinical and clinical studies are needed to validate its therapeutic potential in the context of degenerative retinal disorders such as AMD.

Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A.

The failure of blood vessels to revascularize ischemic neural tissue represents a significant challenge for vascular biology. Examples include proliferative retinopathies (PRs) such as retinopathy of prematurity and proliferative diabetic retinopathy, which are the leading causes of blindness in children and working-age adults. PRs are characterized by initial microvascular degeneration, followed by a compensatory albeit pathologic hypervascularization mounted by the hypoxic retina attempting to reinstate metabolic equilibrium. Paradoxically, this secondary revascularization fails to grow into the most ischemic regions of the retina. Instead, the new vessels are misdirected toward the vitreous, suggesting that vasorepulsive forces operate in the avascular hypoxic retina. In the present study, we demonstrate that the neuronal guidance cue semaphorin 3A (Sema3A) is secreted by hypoxic neurons in the avascular retina in response to the proinflammatory cytokine IL-1ß. Sema3A contributes to vascular decay and later forms a chemical barrier that repels neo-vessels toward the vitreous. Conversely, silencing Sema3A expression enhances normal vascular regeneration within the ischemic retina, thereby diminishing aberrant neovascularization and preserving neuroretinal function. Overcoming the chemical barrier (Sema3A) released by ischemic neurons accelerates the vascular regeneration of neural tissues, which restores metabolic supply and improves retinal function. Our findings may be applicable to other neurovascular ischemic conditions such as stroke.

[Iron and regulatory proteins in the normal and pathological retina]. / Fer et protéines régulatrices dans la rétine normale et pathologique.

Iron is necessary for cell metabolism, but excess iron can be toxic Iron can generate oxygen free radicals through the Fenton reaction. Iron accumulation has been observed in the retina of patients with age-related macular degeneration (AMD). We have shown its accumulation in photoreceptor segments in two animal models of genetic retinal degeneration (RCS rats and Rd10 mice). In these rodents, hTf, injected intraperitoneally or expressed by genetic modification, delayed photoreceptor degeneration. Our studies highlight the therapeutic potential of Tf in degenerative processes such as retinitis pigmentosa and AMD.

Identifying positive impression management using the MMPI-2 and the MMPI-2-RF: A meta-analysis.

Objective:Individuals may be motivated to conceal or minimize psychological symptoms and engage in positive impression management (PIM) in order to achieve desired outcomes across high stakes contexts (e.g. fitness for duty evaluations, pre-sentencing assessments, medical procedure evaluations, civil commitment). Despite the importance of this topic, the most recent meta-analysis of the MMPI-2, a widely used instrument for detecting PIM, was conducted more than two decades ago. Method:Using a Robust Variance Estimation method, this meta-analysis synthesized the results of 27 studies that examined the MMPI-2 (k = 22) and MMPI-2-RF (k = 5) validity scales' ability to discriminate individuals who engage in PIM from genuine responders, with a particular focus on the L, K, and S scales. Results:The MMPI-2 L scale produced the largest effect size (g = 1.30), whereas the MMPI-2-RF L-r scale effect size was moderate (g = 1.16). Moderate effect sizes were also found for the K (g = 1.01) and K-r (g = 1.21) scales, and for the MMPI-2 S scale (g = 1.23). Conclusions: Effect sizes did not significantly vary between the two versions of the MMPI. Findings suggest that both versions of the MMPI have demonstrated utility in identifying PIM, but clinicians should interpret T scores conservatively to account for the modest elevations associated with defensiveness. Findings are discussed in the context of the recently released MMPI-3.

Comparing the Ability of MMPI-2 and MMPI-2-RF Validity Scales to Detect Feigning: A Meta-Analysis.

Several meta-analyses of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) have examined these instruments' ability to detect symptom exaggeration or feigning. However, limited research has directly compared whether the scales across these two instruments are equally effective. This study used a moderated meta-analysis to compare 109 MMPI-2 and 41 MMPI-2-RF feigning studies, 83 (56.46%) of which were not included in previous meta-analyses. Although there were differences between the two test versions, with most MMPI-2 validity scales generating larger effect sizes than the corresponding MMPI-2-RF scales, these differences were not significant after controlling for study design and type of symptoms being feigned. Additional analyses showed that the F and Fp-r scales generated the largest effect sizes in identifying feigned psychiatric symptoms, while the FBS and RBS were better at detecting exaggerated medical symptoms. The findings indicate that the MMPI-2 validity scales and their MMPI-2-RF counterparts were similarly effective in differentiating genuine responders from those exaggerating or feigning psychiatric and medical symptoms. These results provide reassurance for the use of both the MMPI-2 and MMPI-2-RF in settings where symptom exaggeration or feigning is likely. Findings are discussed in the context of the recently released MMPI-3.

Understanding the Victimization-Delinquency Overlap Among Latino Adolescents: The Role of Cultural and Mental Health Factors.

The aim of this analysis was to evaluate whether cultural factors and mental health variables distinguish Latino youth who are delinquent-victims, primarily victims, or primarily delinquent. This study used data from the Dating Violence among Latino Adolescents (DAVILA) Study, which surveyed 1,525 Latino youth and queried participants about past year victimization, delinquency, psychological distress, and cultural factors. Using multinomial logistic regression, we evaluated whether these variables differentiated youth who were delinquent-victims, primarily victims, primarily delinquent, or neither delinquent nor victims. Results suggest that delinquent-victim Latino youth are differentiated from other groups primarily by the degree of familial support and anger/hostility. Other cultural and mental health variables do not appear to differentiate the groups, suggesting a greater degree of similarity among them based on the variables used in the analysis. The results indicate that Latino youth that are victimized and engage in delinquent behavior are primarily differentiated by the degree of anger/hostility they experience. Familial support, as has been seen with non-Latino groups, appears to present a significant protective quality and likely can serve as a prevention strategy, particularly for delinquent-victim youth. Study limitations include challenges with retrospective self-report and sampling using RDD methodologies.

Comparative Analysis of Urso- and Tauroursodeoxycholic Acid Neuroprotective Effects on Retinal Degeneration Models.

Ursodeoxycholic (UDCA) and tauroursodeoxycholic (TUDCA) acids have shown neuroprotective properties in neurodegenerative diseases, but differential effects of the two bile acids have been poorly explored. The aim of this study was to evaluate the neuroprotective effects of UDCA versus TUDCA in a neuroretinal degeneration model and to compare transcriptionally regulated pathways. The WERI-Rb-1 human cone-like cell line and retinal explants were exposed to albumin and TUDCA or UDCA. Viability, cell death, and microglial activation were quantified. Transcriptionally regulated pathways were analyzed after RNA sequencing using the edgeR bioconductor package. Pre-treatment of cone-like cells with UDCA or TUDCA significantly protected cells from albumin toxicity. On retinal explants, either bile acid reduced apoptosis, necroptosis, and microglia activation at 6 h. TUDCA induced the regulation of 463 genes, whilst 31 genes were regulated by UDCA. Only nineteen common genes were regulated by both bile acids, mainly involved in iron control, cell death, oxidative stress, and cell metabolism. As compared to UDCA, TUDCA up-regulated genes involved in endoplasmic reticulum stress pathways and down-regulated genes involved in axonal and neuronal development. Either bile acid protected against albumin-induced cell loss. However, TUDCA regulated substantially more neuroprotective genes than UDCA.

NK- and T-cell granzyme B and K expression correlates with age, CMV infection and influenza vaccine-induced antibody titres in older adults.

Granzymes are a family of serine-proteases that act as critical mediators in the cytolytic and immunomodulatory activities of immune cells such as CD8+ T-cells and natural killer (NK) cells. Previous work indicates that both granzyme B (GZB) and K (GZK) are increased with age in CD8+ T-cells, and in the case of GZB, contribute to dysfunctional immune processes observed in older adults. Here, we sought to determine how GZB and GZK expression in NK-cells, and CD4+, CD8+, and gamma-delta T-cells, quantified in terms of positive cell frequency and mean fluorescence intensity (MFI), differed with age, age-related health-traits and the antibody response to high-dose influenza vaccine. We found that the frequency and MFI of GZB-expressing NK-cells, and CD8+ and Vδ1+ T-cells, and GZK-expressing CD8+ T-cells was significantly higher in older (66-97 years old; n = 75) vs. younger (24-37 years old; n = 10) adults by up to 5-fold. There were no significant associations of GZB/GZK expression with sex, frailty or plasma levels of TNF or IL-6 in older adults, but those who were seropositive for cytomegalovirus (CMV) exhibited significantly higher frequencies of GZB+ NK-cells, and CD4+, CD8+ and Vδ1+ T-cells, and GZK+ CD8+ T-cells (Cohen's d = .5-1.5). Pre-vaccination frequencies of GZB+ NK-cells were positively correlated with vaccine antibody responses against A/H3N2 (d = .17), while the frequencies of GZK+ NK and CD8+ T-cells were inversely associated with A/H1N1 (d = -0.18 to -0.20). Interestingly, GZK+ NK-cell frequency was inversely correlated with pre-vaccination A/H1N1 antibody titres, as well as those measured over the previous 4 years, further supporting a role for this subset in influencing vaccine antibody-responses. These findings further our understanding of how granzyme expression in different lymphoid cell-types may change with age, while suggesting that they influence vaccine responsiveness in older adults.