Class IA PI3Ks regulate subcellular and functional dynamics of IDO1.

Knowledge of a protein's spatial dynamics at the subcellular level is key to understanding its function(s), interactions, and associated intracellular events. Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic enzyme that controls immune responses via tryptophan metabolism, mainly through its enzymic activity. When phosphorylated, however, IDO1 acts as a signaling molecule in plasmacytoid dendritic cells (pDCs), thus activating genomic effects, ultimately leading to long-lasting immunosuppression. Whether the two activities-namely, the catalytic and signaling functions-are spatially segregated has been unclear. We found that, under conditions favoring signaling rather than catabolic events, IDO1 shifts from the cytosol to early endosomes. The event requires interaction with class IA phosphoinositide 3-kinases (PI3Ks), which become activated, resulting in full expression of the immunoregulatory phenotype in vivo in pDCs as resulting from IDO1-dependent signaling events. Thus, IDO1's spatial dynamics meet the needs for short-acting as well as durable mechanisms of immune suppression, both under acute and chronic inflammatory conditions. These data expand the theoretical basis for an IDO1-centered therapy in inflammation and autoimmunity.

Loss of Phosphatidylinositol 3-Kinase Activity in Regulatory T Cells Leads to Neuronal Inflammation.

Class I PI3K enzymes are critical for the maintenance of effective immunity. In T cells, PI3Kα and PI3Kδ are activated by the TCR and costimulatory receptors, whereas PI3Kγ is activated by G protein-coupled chemokine receptors. PI3Kδ is a key regulator of regulatory T (Treg) cell function. PI3K isoform-selective inhibitors are in development for the treatment of diseases associated with immune dysregulation, including chronic inflammatory conditions, cancer, and autoimmune diseases. Idelalisib (PI3Kδ), alpelisib (PI3Kα), duvelisib (PI3Kδ/γ), and copanlisib (pan-PI3K) have recently been approved for use in cancer treatment. Although effective, these therapies often have severe side effects associated with immune dysregulation and, in particular, loss of Treg cells. Therefore, it is important to gain a better understanding of the relative contribution of different PI3K isoforms under homeostatic and inflammatory conditions. Experimental autoimmune encephalitis is a mouse model of T cell-driven CNS inflammation, in which Treg cells play a key protective role. In this study, we show that PI3Kδ is required to maintain normal Treg cell development and phenotype under homeostatic conditions but that loss of PI3Kδ alone in Treg cells does not lead to autoimmunity. However, combined loss of PI3Kα and PI3Kδ signaling resulted in increased experimental autoimmune encephalitis disease severity. Moreover, mice lacking PI3Kα and PI3Kδ in Treg cells developed spontaneous peripheral nerve inflammation. These results show a key role for PI3K signaling in Treg cell-mediated protection against CNS inflammation.

Muddying the waters? A false positive case of autoimmune psychosis.

OBJECTIVE: To discuss challenges with the diagnosis of autoimmune psychosis (AP) in people with chronic psychotic disorders. METHOD: We present a case of a 23-year-old man with an exacerbation of treatment-refractory psychosis after receiving intravenous immunoglobulin (IVIG) for suspected AP, diagnosed 4 years after the onset of psychosis. We highlight the diagnostic and management challenges in such cases. RESULTS: The diagnosis of AP in people with long-standing illness relies on the interpretation of non-specific clinical and laboratory findings in individuals with psychosocial problems and challenges of acceptance and adherence to complex medical investigations and treatments. Equivocal results from investigations undertaken without logical clinical reasoning can lead to inappropriate interventions that are costly and can cause iatrogenic harm. CONCLUSION: Psychiatrists should restrict screening for antineuronal antibodies in people with chronic psychosis to those with higher risk features such as persistent treatment refractory symptoms with concurrent neurological signs and symptoms. Further research informing the clinical circumstances for antineuronal antibody testing is needed.

Needs and health care costs in old age: a longitudinal perspective: results from the AgeMooDe study.

Background: The current study aimed to identify whether needs are associated with health care costs in late life longitudinally.Methods: Data were gathered from two waves (at baseline, n = 1199; at follow-up, n = 958) of a multicenter prospective cohort study ('Late-life depression in primary care: needs, health care utilization and costs', AgeMooDe) in Germany. Individuals aged 75 years and above were recruited via general practitioners. The 'Camberwell Assessment of Need for the Elderly' (CANE) was used to assess needs. Based on a questionnaire, the health-related resource use was assessed retrospectively from a societal perspective. The assessment covered outpatient services, inpatient treatment, pharmaceuticals, as well as formal and informal nursing care. Random effects regressions were used.Results: Regressions showed that the number of 'no needs' is inversely associated with total health care costs from a societal perspective (ß = -584.0, p < .001). When a health care perspective was adopted, this association was also significant (ß = -298.8, p < .001). The association between needs and health care costs persisted in all health care sectors considered in this study.Limitations: It might be difficult to generalize our findings to individuals residing in institutional settings.Conclusion: Adjusting for several potential confounders (e.g. sociodemographic and health-related factors), our study showed that needs - quantified using the CANE - are important for health care costs. Interventions should be developed to reduce needs in late life. These interventions may be beneficial for the health care system.

Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality following allotransplant. Activated donor effector T cells can differentiate into pathogenic T helper (Th)-17 cells and germinal center (GC)-promoting T follicular helper (Tfh) cells, resulting in cGVHD. Phosphoinositide-3-kinase-δ (PI3Kδ), a lipid kinase, is critical for activated T cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3Kδ activity in donor T cells that become Tfh cells is required for cGVHD in a nonsclerodermatous multiorgan system disease model that includes bronchiolitis obliterans (BO), dependent upon GC B cells, Tfhs, and counterbalanced by T follicular regulatory cells, each requiring PI3Kδ signaling for function and survival. Although B cells rely on PI3Kδ pathway signaling and GC formation is disrupted resulting in a substantial decrease in Ig production, PI3Kδ kinase-dead mutant donor bone marrow-derived GC B cells still supported BO cGVHD generation. A PI3Kδ-specific inhibitor, compound GS-649443, that has superior potency to idelalisib while maintaining selectivity, reduced cGVHD in mice with active disease. In a Th1-dependent and Th17-associated scleroderma model, GS-649443 effectively treated mice with active cGVHD. These data provide a foundation for clinical trials of US Food and Drug Administration (FDA)-approved PI3Kδ inhibitors for cGVHD therapy in patients.

Stroke patients' and non-professional coaches' experiences with home-based constraint-induced movement therapy: a qualitative study.

OBJECTIVE: To investigate the experiences of chronic stroke patients and non-professional coaches with home-based constraint-induced movement therapy (homeCIMT). DESIGN: Qualitative study embedded within a cluster randomized controlled trial investigating the efficacy of homeCIMT to improve the use of the affected arm in daily activities. SETTING: Patients' home environment. PARTICIPANTS: 13 stroke patients and 9 non-professional coaches' alias family members who had completed the four-week homeCIMT programme in the context of the HOMECIMT trial. INTERVENTIONS: Semi-structured interviews; qualitative data were analysed using the methodology of the hermeneutic phenomenological data analysis. RESULTS: We identified six themes in the qualitative analysis describing the experiences of patients and non-professional coaches with homeCIMT: (1) homeCIMT can be integrated into everyday life with varying degrees of success; (2) training together may produce positive experiences as well as strain; (3) self-perceived improvements during and following homeCIMT; (4) using the affected arm in everyday life is challenging; (5) subjective evaluation of and experiences with homeCIMT-specific exercises; and (6) impact of professional therapists' guidance and motivation during homeCIMT. Statements regarding theme five and six were only provided by patients, whereas the other themes contain both, the experiences of stroke patients and non-professional coaches. CONCLUSION: Patients' and non-professional coaches' narratives offer a detailed insight into the manifold experiences with the practical implementation of homeCIMT that may help improve implementing the homeCIMT programme and similar approaches involving increased training duration and intensity and/or involvement of family members.

A qualitative study on older primary care patients' perspectives on depression and its treatments - potential barriers to and opportunities for managing depression.

BACKGROUND: Depression is one of the most common mental disorders in old age and is associated with various negative health consequences for the affected individual. Studies suggest that patients' views on depression have an impact on help-seeking behaviour and treatment. It is thus important to investigate the patient's perspective in order to ascertain optimum management of depression in late life. However, studies on depression and its treatment exploring the perspectives of primary care patients 75 years or older, are rare. METHODS: Qualitative data was collected in semi-structured interviews with 12 primary care patients 75 years of age or older with symptoms of depression. Data was analysed using qualitative content analysis. RESULTS: The study's results show the multifaceted views on and treatment of depression in primary care patients 75 years of age or older. Some patients seemed well informed about depression and believed in the efficacy of different treatments, such as medications or psychotherapy. However, some individuals had misconceptions about depression and its treatments. Patients mentioned that they would rather avoid talking about depression within their social network, in part of fear of negative reactions. Furthermore, participants believed that other people had little understanding for people with depression. Patients had different views on the relevance of the general practitioner's (GP) role in treating depression; some patients believed that the GP had little importance in the treatment of depression. CONCLUSIONS: This study identified positive views of primary care patients 75 years of age or older towards depression as well as views that might hinder optimal treatments. Exemplary implications for an improved management of depression are: educating older adults about depression via age-specific information and having professionals encourage patients in believing that depression is a recognised disorder.

Unmet needs in the depressed primary care elderly and their relation to severity of depression: results from the AgeMooDe study.

OBJECTIVES: This study aims at examining the distribution of unmet environmental, physical, social and psychological care needs in a sample of the oldest old primary care patients with different levels of depression severity. Furthermore, the objective of this study was to analyze the association between specific unmet care needs and severity of depression. METHOD: The sample of patients aged 75 years (n = 202) and more was derived from the multicenter prospective cohort study AgeMooDe ('Late-life depression in primary care: Needs, health care utilization and costs'). Patients were assessed via structured clinical interviews containing the German version of the Camberwell Assessment of Need for the Elderly (CANE) and the German Hospital Anxiety and Depression Scale (HADS-D). Descriptive statistics, Spearman correlation coefficients and binary logistic regression analyses were computed. RESULTS: Unmet needs appeared to be substantially higher in the patient group with higher levels of depression severity according to the HADS-D score. Overall, there was weak positive linear correlation between depression and CANE total unmet needs. Except of the physical unmet needs category, all other CANE care categories showed little to moderate positive linear correlations with depression according to the HADS-D score. Depression and psychological unmet needs showed the strongest of all correlations, followed by social unmet needs. The binary logistic regression analysis revealed that patients having psychological unmet needs were 4.8 times more likely diagnosed with a probable depression. CONCLUSION: Systematic needs assessment, especially psychological needs, may play a crucial role in the course of prevention and effective treatment of late-life depression in the primary care context.

The Impact of Depressive Symptoms on Healthcare Costs in Late Life: Longitudinal Findings From the AgeMooDe Study.

OBJECTIVE: To examine whether depressive symptoms affect healthcare costs in old age longitudinally. DESIGN: Multicenter prospective observational cohort study (two waves with nt1 = 1,195 and nt2 = 951) in Germany. SETTING: Community. PARTICIPANTS: Participants aged 75 years and older recruited via general practitioners. MEASUREMENTS: Depressive symptoms were assessed by the Geriatric Depression Scale (GDS). The health-related resource use was measured retrospectively from a societal perspective based on a questionnaire, covering outpatient services, inpatient treatment, pharmaceuticals, as well as formal and informal nursing care. Hybrid regression models were used to determine the between- and within-effect of depressive symptoms on healthcare costs, adjusting for important covariates. RESULTS: Six-month total cost increased from €3,090 (t1) to €3,748 (t2). The hybrid random effects models showed that individuals with more depressive symptoms had higher healthcare costs compared with individuals with less depressive symptoms (between-effect). Moreover, an intra-individual increase in depressive symptoms increased healthcare costs by €539.60 (within-effect) per symptom on GDS. CONCLUSIONS: Our findings emphasize the economic importance of depressive symptoms in old age. Appropriate interventions to treat depressive symptoms in old age might also be a promising strategy to reduce healthcare costs.

Profiles of met and unmet care needs in the oldest-old primary care patients with depression - results of the AgeMooDe study.

BACKGROUND: Unmet care needs have been associated with an increased risk of depression in old age. Currently, the identification of profiles of met and unmet care needs associated with depressive symptoms is pending. Therefore, this exploratory study aimed to identify profiles of care needs and analyze associated factors in oldest-old patients with and without depression. METHODS: The sample of 1092 GP patients aged 75+ years is based on the multicenter study "Late-life depression in primary care: needs, health care utilization and costs (AgeMooDe)". Depression (i.e. clinically meaningful depressive symptoms) was determined using the Geriatric Depression Scale (GDS) (cutoff score ≥ 4). Needs of patients were assessed using the Camberwell Assessment of Need for the Elderly (CANE). Associated sociodemographic and clinical factors were examined, and latent class analysis identified the need profiles. RESULTS: The main result of the study indicates three need profiles: 'no needs', 'met physical needs', and 'unmet social needs'. Members of the 'met physical needs' (OR = 3.5, 95 %-CI: 2.5-4.9) and 'unmet social needs' (OR = 17.4, 95 %-CI: 7.7-39.7) profiles were significantly more likely to have depression compared to members of the 'no needs' profile. LIMITATIONS: Based on the cross-sectional design, no conclusions can be drawn about the causality or direction of the relationships between the variables. CONCLUSIONS: The study results provide important insights for the establishment of needs-based interventions for GPs. Particular attention should be paid to the presence of unmet social needs in the oldest-old GP patients with underlying depressive symptoms.

A review of the use of clozapine levels to guide treatment and determine cause of death.

OBJECTIVE: To review the literature to examine the use of clozapine levels to (i) guide therapy and prevent toxicity in clinical care and (ii) determine cause of death in post-mortem examination of patients who were treated with clozapine. METHODS: MEDLINE was searched in December 2010 using the following keywords: 'clozapine levels', 'clozapine and toxicity', 'clozapine and death', 'clozapine and mortality' and 'post-mortem redistribution'. Data was also collected from the 2010 MIMS Annual. RESULTS: The literature reported significant variation in clozapine levels attained with any given dose, and considerable variability in the clinical response achieved at any given clozapine level. The lowest effective clozapine levels ranged from 250 to 550 µg/L, while the recommended upper limit to prevent toxicity varied from 600 to 2000 µg/L. There was minimal correlation between clozapine levels and side effects, with the exception of sedation, hypotension and seizure activity. The risk of seizures increased with plasma clozapine levels greater than 600 µg/L or rapid upward titration. In addition to prescribed dose, there are many factors that influence plasma clozapine levels. After death, the process of post-mortem drug redistribution resulted in 3.00 to 4.89 times increases in clozapine levels in central blood vessels and 1.5 fold increases in peripheral vessels compared to ante-mortem levels. CONCLUSIONS: The exact range of clozapine levels that corresponds to toxicity remains unclear. However, levels between 350 µg/L and 1000 µg/L achieved with gradual upward titration are more likely to be effective and less likely to cause toxicity. Ongoing clozapine level monitoring is indicated, especially when (i) prescribing higher doses (> 600 mg/day) of clozapine, (ii) there has been a change in a patient's concomitant pharmacotherapy or cigarette use and (iii) there has been a suboptimal response to treatment. The use of post-mortem clozapine levels to determine clozapine toxicity as a cause of death is unreliable.

Depressive Symptoms and Healthcare Utilization in Late Life. Longitudinal Evidence From the AgeMooDe Study.

Objective: The aim of this study was to investigate the longitudinal impact of depressive symptoms on utilization of healthcare in terms of GP visits as well as specialist visits and hospital admission in late life among community-dwelling individuals. Methods: Longitudinal data (baseline and follow-up) were derived from the German multicentre, prospective cohort study "Late-life depression in primary care: needs, health care utilization and costs" study (AgeMooDe). At baseline, n = 1,230 patients aged 75 years and older were recruited from primary care practices. Main outcomes of interest were use of health care services: the number of GP visits, the number of medical specialist visits, and hospital admission. We used the Geriatric Depression Scale (GDS-15) to measure depression. Outcomes were analyzed with multilevel random intercept negative binominal regression and logistic random-effects models. Results: At baseline (n = 1,191), mean age was 80.7 (SD 4.6) years, 62.9% were female, and 196 individuals (16.5%) had depression (GDS-15 ≥6). Our longitudinal analyses indicated that older individuals with more depressive symptoms visited their GP more often (IRR=1.03; CI [1.01-1.04], p < 0.001), were visiting medical specialists more frequently (IRR=1.03; CI [1.01-1.04], p < 0.01), and had higher odds of being hospitalized (OR=1.08; CI [1.02-1.13], p < 0.01). Conclusions: Based on this large longitudinal study we showed that, after adjustment for important covariates, older individuals with more depressive symptoms had higher health care utilization over time. They visited their GP and specialists more frequently and they had higher odds of being hospitalized. This may suggest that higher utilization of specialist care and increased likelihood of being hospitalized may be also attributable to unspecific symptoms or symptoms that are elevated through depressive symptoms.

The GPCR adaptor protein norbin suppresses the neutrophil-mediated immunity of mice to pneumococcal infection.

Streptococcal pneumonia is a worldwide health problem that kills ∼2 million people each year, particularly young children, the elderly, and immunosuppressed individuals. Alveolar macrophages and neutrophils provide the early innate immune response to clear pneumococcus from infected lungs. However, the level of neutrophil involvement is context dependent, both in humans and in mouse models of the disease, influenced by factors such as bacterial load, age, and coinfections. Here, we show that the G protein-coupled receptor (GPCR) adaptor protein norbin (neurochondrin, NCDN), which was hitherto known as a regulator of neuronal function, is a suppressor of neutrophil-mediated innate immunity. Myeloid norbin deficiency improved the immunity of mice to pneumococcal infection by increasing the involvement of neutrophils in clearing the bacteria, without affecting neutrophil recruitment or causing autoinflammation. It also improved immunity during Escherichia coli-induced septic peritonitis. It increased the responsiveness of neutrophils to a range of stimuli, promoting their ability to kill bacteria in a reactive oxygen species-dependent manner, enhancing degranulation, phagocytosis, and the production of reactive oxygen species and neutrophil extracellular traps, raising the cell surface levels of selected GPCRs, and increasing GPCR-dependent Rac and Erk signaling. The Rac guanine-nucleotide exchange factor Prex1, a known effector of norbin, was dispensable for most of these effects, which suggested that norbin controls additional downstream targets. We identified the Rac guanine-nucleotide exchange factor Vav as one of these effectors. In summary, our study presents the GPCR adaptor protein norbin as an immune suppressor that limits the ability of neutrophils to clear bacterial infections.

To what extent does therapy of chronic stroke patients address participation? A content analysis of ambulatory physical and occupational therapy based on the International Classification of Functioning, Disability, and Health framework.

Purpose: The study aim was to analyze whether ambulatory therapy of chronic stroke patients contains elements that specifically address "Activity and participation", and to what extent participation as a major goal in rehabilitation is realized in ambulatory care.Method: Qualitative and quantitative content analysis of standard therapy of 71 chronic stroke patients with upper limb impairment. 469 statements on therapy of 34 therapists were analyzed using data-driven and concept-driven coding based on the International Classification of Functioning, Disability and Health framework.Results: Almost half of therapy provided to stroke patients was related to "Upper extremity" (47.5%), as one out of seven identified main categories. Regarding International Classification of Functioning, Disability, and Health framework, 75.1% of therapeutic practices in ambulatory therapy covered "Body functions," but only 13.2% addressed "Activities and participation". Some statements contained specific therapeutic concepts (9.4%) or isolated notes (2.1%) and were not linkable to the International Classification of Functioning, Disability and Health framework.Conclusions: Ambulatory therapy of chronic stroke patients is related, in part, to participation. There is potential for an increase in participation by applying therapeutic approaches, which actively involve the patients in goal-setting and therapeutic exercises to specifically address activities and participation.Implications for rehabilitationTo realize participation as a major goal in the rehabilitation process ambulatory therapy of chronic stroke patients, one should focus on therapeutic approaches and exercises that specifically address activities and participation.Structured goal-setting, which actively involve patients, can be used to identify goals relevant to individual activities and participation.

Late-Life Depressive Symptoms Are Associated With Functional Impairment Cross-sectionally and Over Time: Results of the AgeMooDe Study.

OBJECTIVES: This study examines the relationship between late-life depressive symptoms, cognitive and functional impairment in a cohort of very old community-based participants. METHODS: A sample of 1,226 primary care patients was assessed at baseline (Mage = 80.6 years). Statistical analyses were conducted using baseline and 12-month follow-up data. RESULTS: At baseline, depressed participants showed minor cognitive deficits compared with nondepressed participants, whereas functional deficits were pronounced. Depressive symptoms and global cognition were not associated longitudinally. In contrast, follow-up functional impairment was predicted by baseline level and increase of depressive symptoms between baseline and follow-up. Reversely, follow-up depressive symptoms were predicted by functional decline between baseline and follow-up, whereas baseline functional status was not predictive. DISCUSSION: Depressive symptoms and global cognitive function were not associated longitudinally, but level and increase of depressive symptoms over time predicted functional impairment after 1 year. Interventions to reduce depressive symptoms, or to encourage coping strategies might be promising to reduce functional impairment. Elevated follow-up depressive symptoms were only predicted by functional decline, supposedly emphasizing that incident functional impairment might be associated with an acute increase of depressive symptoms. Psychological adjustment processes were not examined, but might be targeted in future.

Are older men more vulnerable to depression than women after losing their spouse? Evidence from three German old-age cohorts (AgeDifferent.de platform).

BACKGROUND: Old age is accompanied by a higher risk of losing a spouse. This study aims to longitudinally investigate the effect of widowhood on depression severity with a special focus on sex differences. We examine depression before and after widowhood in men and women separately to investigate which sex is at greater risk after losing a spouse. METHODS: Data came from the AgeDifferent.de platform, which includes three pooled old age cohort studies. In order to examine factors associated with depression over time, we applied a linear hybrid mixed-effects regression model for the overall sample and analysed additional separate models for men and women. RESULTS: Of 2470 respondents (mean age at baseline 79.2 (SD 3.64) years), 1256 were men. In total, 209 men and 332 women experienced spousal bereavement after baseline. In general, both sexes showed higher depression severity after widowhood. However, there were significant sex differences. Widowed men were more prone to subsequent depression than widowed women. In terms of depression severity, widowed men differed significantly compared to non-widowed men; however, this was not the case for women. LIMITATION: We harmonized three cohort studies which used different measurement scales for depression and different recruitment procedures. CONCLUSION: Our study showed that although both genders suffer from losing a spouse, men are more prone to subsequently develop depressive symptoms. Raising the awareness among practitioners for sex-specific differences as well as developing tailored interventions for both widowed men and women should be considered.

Categorical and dimensional perspectives on depression in elderly primary care patients - Results of the AgeMooDe study.

An accurate diagnosis is essential for the management of late-life depression in primary care. This study aims to (1) provide information on the agreement on depression diagnoses between general practitioners (GPs), dimensional tools (Geriatric Depression Scale [GDS], Hospital Anxiety and Depression Scale [HADS]) and a categorical tool (Structured Clinical Interview for DSM-IV criteria [SCID]) and (2) identify factors associated with different diagnoses. As part of the multicenter study "Late-life depression in primary care: needs, health care utilization and costs (AgeMooDe)" a sample of 1113 primary care patients aged 75 years and older was assessed. The proportion of depression was 24.3% according to GPs, 21.8% for the GDS, 18.9% for the HADS and 8.2% for the SCID. Taking GDS, HADS and SCID as reference standards, recognition of GPs was 47%, 48% and 63%. Cohen's Kappa values indicate slight to moderate agreement between diagnoses. Multinomial logistic regression models showed that patient related factors of depression were anxiety, intake of antidepressants, female gender, a low state of health, intake of medication for chronic diseases and functional impairment. GPs performed better at ruling out depression than ruling in depression. High levels of disagreement between different perspectives on depression indicate that they may be sensitive to different aspects of depression.

PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.

Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world-wide. Antibody-mediated immune responses can confer protection against repeated exposure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19+B220- B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased susceptibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target.

Multi-tissue DNA methylation age predictor in mouse.

BACKGROUND: DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse. RESULTS: We have generated a comprehensive set of genome-scale base-resolution methylation maps from multiple mouse tissues spanning a wide range of ages. Many CpG sites show significant tissue-independent correlations with age which allowed us to develop a multi-tissue predictor of age in the mouse. Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks and has similar properties to the recently described human epigenetic clock. Using publicly available datasets, we find that the mouse clock is accurate enough to measure effects on biological age, including in the context of interventions. While females and males show no significant differences in predicted DNA methylation age, ovariectomy results in significant age acceleration in females. Furthermore, we identify significant differences in age-acceleration dependent on the lipid content of the diet. CONCLUSIONS: Here we identify and characterise an epigenetic predictor of age in mice, the mouse epigenetic clock. This clock will be instrumental for understanding the biology of ageing and will allow modulation of its ticking rate and resetting the clock in vivo to study the impact on biological age.