Mitochondrial respiratory capacity is a critical regulator of CD8⁺ T cell memory development

CD8+ T cells undergo major metabolic changes upon activation, but how metabolism influences the establishment of long-lived memory T cells after infection remains a key question. We have shown here that CD8+ memory T cells, but not CD8+ T effector (Teff) cells, possessed substantial mitochondrial spare respiratory capacity (SRC). SRC is the extra capacity available in cells to produce energy in response to increased stress or work and as such is associated with cellular survival. We found that interleukin-15 (IL-15), a cytokine critical for CD8+ memory T cells, regulated SRC and oxidative metabolism by promoting mitochondrial biogenesis and expression of carnitine palmitoyl transferase (CPT1a), a metabolic enzyme that controls the rate-limiting step to mitochondrial fatty acid oxidation (FAO). These results show how cytokines control the bioenergetic stability of memory T cells after infection by regulating mitochondrial metabolism

Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells

TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources. We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents activation and leads to premature cell death. However, it remained unclear why the decrease in OXPHOS occurs under these circumstances. Using real-time metabolic flux analysis, in the present study, we show that mitochondrial activity is lost progressively after activation by TLR agonists in inflammatory blood monocyte–derived DCs that express inducible NO synthase. We found that this is because of inhibition of OXPHOS by NO and that the switch to glycolysis is a survival response that serves to maintain ATP levels when OXPHOS is inhibited. Our data identify NO as a profound metabolic regulator in inflammatory monocyte–derived DCs

CN and HCN in Dense Interstellar Clouds

We present a theoretical investigation of CN and HCN molecule formation in dense interstellar clouds. We study the gas-phase CN and HCN production efficiencies from the outer photon-dominated regions (PDRs) into the opaque cosmic-ray dominated cores. We calculate the equilibrium densities of CN and HCN, and of the associated species C+, C, and CO, as functions of the far-ultraviolet (FUV) optical depth. We consider isothermal gas at 50 K, with hydrogen particle densities from 10^2 to 10^6 cm^-3. We study clouds that are exposed to FUV fields with intensities 20 to 2*10^5 times the mean interstellar FUV intensity. We assume cosmic-ray H2 ionization rates ranging from 5*10^-17 s^-1, to an enhanced value of 5*10^-16 s^-1. We also examine the sensitivity of the density profiles to the gas-phase sulfur abundance.Comment: Accepted for publication in ApJ, 33 pages, 8 figure

The 12-Item Hypoglycemia Impact Profile (HIP12):psychometric validation of a brief measure of the impact of hypoglycemia on quality of life among adults with type 1 or type 2 diabetes

Introduction: The aim of this study was to determine the psychometric properties of the 12-Item Hypoglycemia Impact Profile (HIP12), a brief measure of the impact of hypoglycemia on quality of life (QoL) among adults with type 1 (T1D) or type 2 diabetes (T2D). Research design and methods: Adults with T1D (n=1071) or T2D (n=194) participating in the multicountry, online study, ‘Your SAY: Hypoglycemia’, completed the HIP12. Psychometric analyses were undertaken to determine acceptability, structural validity, internal consistency, convergent/divergent validity, and known-groups validity. Results: Most (98%) participants completed all items on the HIP12. The expected one-factor solution was supported for T1D, T2D, native English speaker, and non-native English speaker groups. Internal consistency was high across all groups (ω=0.91–0.93). Convergent and divergent validity were satisfactory. Known-groups validity was demonstrated for both diabetes types, by frequency of severe hypoglycemia (0 vs ≥1 episode in the past 12 months) and self-treated episodes (<2 vs 2–4 vs ≥5 per week). The measure also discriminated by awareness of hypoglycemia in those with T1D. Conclusions: The HIP12 is an acceptable, internally consistent, and valid tool for assessing the impact of hypoglycemia on QoL among adults with T1D. The findings in the relatively small sample with T2D are encouraging and warrant replication in a larger sample

Changes in attitudes to awareness of hypoglycaemia during a hypoglycaemia awareness restoration programme are associated with avoidance of further severe hypoglycaemia episodes within 24 months: the A2A in HypoCOMPaSS study

Aims/hypothesis: The aims of this study were to assess cognitions relating to hypoglycaemia in adults with type 1 diabetes and impaired awareness of hypoglycaemia before and after the multimodal HypoCOMPaSS intervention, and to determine cognitive predictors of incomplete response (one or more severe hypoglycaemic episodes over 24 months). Methods: This analysis included 91 adults with type 1 diabetes and impaired awareness of hypoglycaemia who completed the Attitudes to Awareness of Hypoglycaemia (A2A) questionnaire before, 24 weeks and 24 months after the intervention, which comprised a short psycho-educational programme with optimisation of insulin therapy and glucose monitoring. Results: The age and diabetes duration of the participants were 48±12 and 29±12 years, respectively (mean±SD). At baseline, 91% reported one or more severe hypoglycaemic episodes over the preceding 12 months; this decreased to <20% at 24 weeks and after 24 months (p=0.001). The attitudinal barrier hyperglycaemia avoidance prioritised (2p=0.250, p=0.001) decreased from baseline to 24 weeks, and this decrease was maintained at 24 months (mean±SD=5.3±0.3 vs 4.3±0.3 vs 4.0±0.3). The decrease in asymptomatic hypoglycaemia normalised from baseline (2p=0.113, p=0.045) was significant at 24 weeks (1.5±0.3 vs 0.8±0.2). Predictors of incomplete hypoglycaemia response (one or more further episodes of severe hypoglycaemia) were higher baseline rates of severe hypoglycaemia, higher baseline scores for asymptomatic hypoglycaemia normalised, reduced change in asymptomatic hypoglycaemia normalised scores at 24 weeks, and lower baseline hypoglycaemia concern minimised scores (all p<0.05). Conclusions/interpretation: Participation in the HypoCOMPaSS RCT was associated with improvements in hypoglycaemia-associated cognitions, with hyperglycaemia avoidance prioritised most prevalent. Incomplete prevention of subsequent severe hypoglycaemia episodes was associated with persistence of the cognition asymptomatic hypoglycaemia normalised. Understanding and addressing cognitive barriers to hypoglycaemia avoidance is important in individuals prone to severe hypoglycaemia episodes. Clinical trials registration: www.isrctn.org: ISRCTN52164803 and https://eudract.ema.europa.eu: EudraCT2009-015396-27. Graphical abstract: [Figure not available: see fulltext.]. (c) 2022, The Author(s)

Hyperglycaemia aversion in type 1 diabetes: A grounded theory study

Objective: Very little is known about the circumstances under which hyperglycaemia aversion develops and is maintained. The present study aimed to identify psychological factors involved in the process of hyperglycaemia aversion and to understand how it affects people's self‐management of type 1 diabetes. Design: Qualitative, in‐depth interviews were used. Methods: A constructivist grounded theory study, using semi‐structured participant interviews, was undertaken to build a theoretical model of the process of hyperglycaemia aversion. Results: Eighteen participants were interviewed. Fifteen were considered hyperglycaemia averse and included in the analysis. A theoretical model was developed to describe and explain processes involved in hyperglycaemia aversion. Many participants held very high standards for themselves and often had a strong preference for control. While some participants described anxiety associated with higher blood glucose, the most proximal driver of their approach was self‐criticism and frustration associated with not meeting their own high standards for blood glucose. A number of attentional processes and beliefs, mostly related to hypoglycaemia, maintained and reinforced their blood glucose preference. Diabetes technology served as an enabler, raiser of standards, and additional critical judge of participants' hyperglycaemia aversion. Conclusions: The trans‐diagnostic concept of emotional over‐control is used to understand the proposed model of processes of hyperglycaemia aversion. The present study offers new insight which will aid clinicians in identifying and supporting those who may be at risk of psychological distress and harm associated with a preference for avoidance of higher blood glucose levels

Infrared spectroscopy of NGC 1068: Probing the obscured ionizing AGN continuum

The ISO-SWS 2.5-45 um infrared spectroscopic observations of the nucleus of the Seyfert 2 galaxy NGC 1068 (see companion paper) are combined with a compilation of UV to IR narrow emission line data to determine the spectral energy distribution (SED) of the obscured extreme-UV continuum that photoionizes the narrow line emitting gas in the active galactic nucleus. We search a large grid of gas cloud models and SEDs for the combination that best reproduces the observed line fluxes and NLR geometry. Our best fit model reproduces the observed line fluxes to better than a factor of 2 on average and is in general agreement with the observed NLR geometry. It has two gas components that are consistent with a clumpy distribution of dense outflowing gas in the center and a more extended distribution of less dense and more clumpy gas farther out that has no net outflow. The best fit SED has a deep trough at ~4 Ryd, which is consistent with an intrinsic Big Blue Bump that is partially absorbed by ~6x10^19 cm^-2 of neutral hydrogen interior to the NLR.Comment: 15 pp, 4 figures, ApJ accepte