Femtosecond Resolution of the Nonballistic Electron Energy Transport in Warm Dense Copper.

The ultrafast electron energy transport is investigated in laser-heated warm dense copper in a high flux regime (2.5±0.7×10^{13} W/cm^{2} absorbed). The dynamics of the electron temperature is retrieved from femtosecond time-resolved x-ray absorption near-edge spectroscopy near the Cu L3 edge. A characteristic time of ∼1 ps is observed for the increase in the average temperature in a 100 nm thick sample. Data are well reproduced by two-temperature hydrodynamic simulations, which support energy transport dominated by thermal conduction rather than ballistic electrons.

Measuring liveweight changes in lactating dairy ewes with an automated walk-over-weighing system.

Monitoring liveweight (LW) is an important part of sound management practices at the individual and flock level (e.g., controlling for nutritional status based on body condition, reproduction, and health-related issues), but it is time consuming and stressful. To our knowledge, no literature has reported on the evaluation of automated weighing systems in dairy sheep as an alternative to conventional static scales. The objective of this research was to evaluate the practical feasibility of using an automated walk-over-weighing (WoW) prototype to measure daily LW changes in dairy ewes without human intervention. We used adult Lacaune dairy ewes in 2 complementary trials conducted indoors. Trial 1 aimed at evaluating the repeatability, precision, and accuracy of LW measures recorded using WoW scales compared with a static scale (the gold standard). Forty-two adult ewes (LW ± standard deviation = 71.3 ± 10.4 kg) were randomly drafted from the main flock and used in a 1-day session. The trial included 3 passages. In each passage, ewes were weighed first on a static scale; once a static position was achieved and LW recorded, they continued the circuit and immediately traversed the WoW scale for an automated LW record. Trial 2 aimed to demonstrate the feasibility of using the WoW device under real-world conditions in a dairy sheep-farming system. The WoW scale was installed in the exit race of the milking parlor and evaluated over 7 wk with adult ewes in mid lactation (n = 93; LW 78.5 ± 8.1 kg). Once the ewes were acclimated to the WoW system, 1 group of ewes (n = 48) continued to receive the same feeding regimen (controls), and the other group (n = 45) underwent a nutritional challenge [challenged; 2 wk of undernutrition and then back to control regimen (refeeding) for 1 wk]. We evaluated the ability of the WoW to detect small changes in LW. We collected LW data (2 weighings per ewe per day) from the WoW after each of the 2 milking sessions (morning and evening). We also obtained LW values by weighing the ewes using a static scale once a week. The automated WoW system showed substantial agreement with the gold standard when assessed using Lin's concordance correlation coefficient and Bland and Altman's method, largely due to high repeatability. The WoW system was adequate for detecting small daily variations in LW during undernutrition and refeeding periods. Misbehaviors resulted in spurious WoW values in trial 2, requiring us to use filtration methods to exclude outlier weights and allow meaningful assessment of small LW changes. The WoW system evaluated here is an alternative to the static scales conventionally used on dairy sheep farms. If sound filtration of raw data is applied, WoW could contribute to the close (daily) monitoring of individual LW without operator intervention (i.e., voluntary weighing) and taking animal welfare into account (i.e., no stress related to the weighing session on static scales).

Two-Color Soft X-Ray Lasing in a High-Density Nickel-like Krypton Plasma.

We report evidence of strong lasing on the 4p-4s transition at 62.7 nm in nickel-like krypton occurring simultaneously with the usual 4d-4p lasing at 32.8 nm. The gain dynamics of both transitions were experimentally and numerically investigated and found comparable. The two-color amplifier was seeded by the same harmonic pulse, therefore producing a short-duration coherent two-color soft x-ray laser pulse. Both transitions offer similar prospects of pulse energy and duration and could lead to the delivery of intense and ultrashort two-color coherent soft x-ray pulses with a controllable delay.

Acquired generalized lipodystrophy under immune checkpoint inhibition.

Immune checkpoint inhibitors are now the standard of care in the treatment of several types of cancer. Cutaneous immune-related adverse events (irAEs) are usually of low grade and reversible, while endocrine irAEs are generally irreversible and managed with hormone replacement therapy. We report a 47-year-old patient, treated with the anti-programmed cell death (PD)1 antibody pembrolizumab for a metastatic melanoma, who developed severe lipodystrophy after 10 months of treatment, characterized by the loss of subcutaneous fat tissue, central obesity and insulin resistance with a decreased leptin level. Histological analysis of a cutaneous biopsy revealed subcutaneous fat cell destruction associated with oedema, the presence of lipophages, and a CD3+ lymphocytic infiltrate involving the panniculus. This led to the diagnosis of anti-PD-1-induced acquired generalized lipodystrophy, after ruling out differential diagnoses (i.e. genetic and systemic autoimmune diseases). No corticosteroids were introduced considering the high risk of inducing severe metabolic complications, and pembrolizumab was discontinued as complete response of the melanoma was achieved. However, after 12 months of follow-up, lipodystrophy and its severe metabolic complications are still ongoing. What's already known about this topic? Anti-programmed cell death (PD)1 agents are now a standard of care in the treatment of several cancers, including melanoma. Endocrine and cutaneous immune-related adverse events (irAEs) are among the most frequent irAEs (14-30% and 30-40%, respectively) in patients treated with immune checkpoint inhibitors. What does this study add? Acquired generalized lipodystrophy can occur during anti-PD1 therapy and is associated with severe metabolic complications. With the increase in anti-PD1 prescription in several cancer types, clinicians must be aware of the whole range of irAEs that may occur.

[Recommendations of the Urolithiasis Committee of the French Urology Association for the management and the treatment of the stone formers patients during the COVID-19 pandemic crisis]. / Recommandations du Comité Lithiase de l'Association Française d'Urologie pour la prise en charge des calculs urinaires durant la crise sanitaire liée à la pandémie à COVID-19.

For the first time, faced with a crisis with an exceptional magnitude due to the COVID-19 pandemic responsible for saturation of emergency services and intensive care units, the urolithiasis committee of the French Urology Association designed the recommendations for care and treatment of stone-forming patients and their treatment during crisis.

High-flux source of coherent XUV pulses for user applications.

We present experimental results obtained at a user-oriented XUV beamline implemented at the ELI Beamlines facility. The coherent XUV radiation is produced via high harmonic generation in gases in a loose focusing geometry. The beamline is designed to be driven by 1 kHz, 100 mJ, 20 fs pulses centered at a wavelength of 830 nm. Results such as XUV spectra, beam wavefront and pulse energy obtained during the beamline commissioning with a commercial 1 kHz, 5 mJ, 40 fs laser system are presented. A unique XUV spectrometer for source characterization designed to reach a very high sensitivity is described in detail, and we demonstrate a novel technique for single-shot and every-shot XUV pulse energy measurement.

Detection of in vivo hepatitis B virus surface antigen mutations-A comparison of four routine screening assays.

An important requirement for a state-of-the-art hepatitis B surface antigen (HBsAg) screening assay is reliable detection of mutated HBsAg. Currently, there is a striking shortage of data regarding the detection rates of in vivo HBsAg mutations for these clinically important assays. Therefore, we compared the detection rates of four commercial HBsAg screening assays using a global cohort of 1553 patients from four continents with known HBV genotypes. These samples, which represent the broadest spectrum of known and novel HBsAg major hydrophilic region (MHR) mutations to date, were analyzed for the presence of HBsAg using the Roche Elecsys® HBsAg II Qualitative, Siemens ADVIA Centaur XP HBsAg II, Abbott Architect HBsAg Qualitative II and DiaSorin Liaison® HBsAg Qualitative assays, respectively. Of the 1553 samples, 1391 samples could be sequenced; of these, 1013 (72.8%) carried at least one of the 345 currently known amino acid substitutions (distinct HBsAg mutation) in the HBsAg MHR. All 1553 patient samples were positive for HBsAg using the Elecsys® HBsAg II Qual assay, with a sensitivity (95% confidence interval) of 99.94% (99.64%-100%), followed by the Abbott Architect 99.81% (99.44%-99.96%), Siemens ADVIA 99.81% (99.44%-99.96%) and DiaSorin Liaison® 99.36% (98.82%-99.69%) assays, respectively. Our results indicate that the Elecsys® HBsAg II Qual assay exhibits the highest sensitivity among the commercial HBsAg screening assays, and demonstrate that its capacity to detect HBV infection is not compromised by HBsAg MHR mutants.

Ketosis-prone atypical diabetes in Cameroonian people with hyperglycaemic crisis: frequency, clinical and metabolic phenotypes.

AIM: It is unclear whether ketosis-prone diabetes is a specific type or a subtype of Type 2 diabetes. We aimed to describe the clinical and metabolic features of ketosis-prone diabetes in a sub-Saharan population. METHODS: We consecutively enrolled and characterized 173 people with non-autoimmune diabetes admitted for hyperglycaemic crisis at the Yaoundé Central Hospital, Cameroon. Blood samples were collected for fasting glucose, HbA1c , lipid profile and C-peptide assays with insulin resistance and secretion estimation by homeostasis model assessment. People were classified as having Type 2 diabetes (n = 124) or ketosis-prone diabetes (n = 49). Ketosis-prone diabetes was sub-classified as new-onset ketotic phase (n = 34) or non-ketotic phase (n = 15). RESULTS: Ketosis-prone diabetes was found in 28.3% of the hyperglycaemic crises. Age at diabetes diagnosis was comparable in Type 2 and ketosis-prone diabetes [48 ± 14 vs 47 ± 11 years; P = 0.13] with a similar sex distribution. Overall BMI was 27.7 ± 13.4 kg/m2 and was ≥ 25 kg/m2 in 55.8% of those taking part, however, 73.5% of those with ketosis-prone diabetes reported weight loss of > 5% at diagnosis. Blood pressure and lipid profile were comparable in both types. Ketosis-prone diabetes in the ketotic phase was characterized by lower insulin secretion and higher serum triglycerides compared with non-ketotic ketosis prone and Type 2 diabetes. Type 2 and ketosis prone diabetes in the non-ketotic phase were comparable in terms of lipid profile, blood pressure, waist-to-hip ratio, BMI and fat mass, insulin secretion and insulin resistance indices. CONCLUSIONS: Ketosis-prone diabetes is likely to be a subtype of Type 2 diabetes with the potential to develop acute insulinopenic episodes.

[Double J stent removal's cost estimate using a re-sterilizable fibroscope in a French private structure]. / Évaluation du coût en structure privée d'une ablation de sonde double J en externe à l'aide d'un fibroscope re-stérilisable.

In front of the arrival of new devices intended to simplify the removal of double J stent, it poses the problem of the knowledge of the real cost of such an ablation under the current conditions of realization. MATERIAL AND METHOD: This is a monocentric economic evaluation of cost and remuneration needed data-gathering of quotation (CCAM, GHS/SE, …), estimate of the associated costs of wear and damping of the endoscopic equipments (endoscopes, cables, …), estimate of the cost of sterilization, estimate of the associated costs to the intervention of staff (Auxiliary nurse [AS] and Nurse [IDE]) with timing of the various tasks. RESULTS: Quotation CCAM JCGE004 (48€) gives access to fixed price SE1 (73.71€ for private clinic, and 75.89€ for public institution) without hospitalization nor anaesthesia. The costs were reported to an act of single double J removal. Concerning the equipments: 4.42€HT for the fibroscopes, graspers, cable and light. The costs of sterilization were: 17.95€HT. The timed workforce's costs were: 7.61-9.51€ for AS and 9.92-10.84€ for IDE. The cost of consumable was about 1.37 €HT, by excluding the common base from the extractions (1.876€HT). The total costs in France in 2016 were thus about 47.4 to 50.496€ including all taxes. CONCLUSIONS: This estimate will be used certainly for reflection on the investments and the future studies of the economic impact of the new devices of extraction, by correlating it of course with the various maintenance contracts from each institution. LEVEL OF PROOF: 4.

Demonstration of a Circularly Polarized Plasma-Based Soft-X-Ray Laser.

We report the first experimental demonstration of a laser-driven circularly polarized soft-x-ray laser chain. It has been achieved by seeding a 32.8 nm Kr ix plasma amplifier with a high-order harmonic beam, which has been circularly polarized using a four-reflector polarizer. Our measurements testify that the amplified radiation maintains the initial polarization of the seed pulse in good agreement with our Maxwell-Bloch modeling. The resulting fully circular soft-x-ray laser beam exhibits a Gaussian profile and yields about 10^{10} photons per shot, fulfilling the requirements for laboratory-scale photon-demanding application experiments.

Impact of the contamination level and the background flora on the growth of Listeria monocytogenes in ready-to-eat diced poultry.

UNLABELLED: The food safety criteria that have been incorporated in European regulation (EC) No2073/2005 (Official Journal of the European Union L, 338, 2005, 1), for Listeria monocytogenes in ready-to eat (RTE) foods, specify a maximum allowable concentration of 100 CFU g(-1) or ml(-1) . Some factors such as pH, salt and modified atmosphere packaging (MAP) are used to prevent the growth of L. monocytogenes in order to comply with the limit. Interactions between background microflora (BM) and L. monocytogenes may limit the growth of L. monocytogenes. The aim of this study was to investigate the mechanisms behind the observed inhibition by natural BM of the growth of L. monocytogenes in ready-to-eat diced poultry meat whose pH and water activity were favourable to its growth. The dynamics of L. monocytogenes and natural BM were therefore monitored in mono-culture and co-culture experiments with various combinations of contamination levels. In the absence of BM, the growth potential of L. monocytogenes depended only on the initial inoculum. With both BM and L. monocytogenes, whatever the combination of concentrations studied, the growth potentials of L. monocytogenes were lower than in a mono-culture through a partial Jameson effect. Thus, the use-by date of this product can be optimized by using models that take into account interactions with BM. SIGNIFICANCE AND IMPACT OF THE STUDY: The study of the growth of Listeria monocytogenes in a diced poultry meat, a matrix whose pH and water activity characteristics are favourable to L. monocytogenes growth, showed that it was inhibited by natural background microflora. This highlights the importance of knowing the product's composition, and in particular the natural background microflora, which can impact the use-by date.

Pronounced reduction of postprandial glucagon by lixisenatide: a meta-analysis of randomized clinical trials.

AIM: Glucagon-like peptide-1 (GLP-1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aimed to investigate the effects of the once-daily prandial GLP-1 receptor agonist lixisenatide on postprandial plasma glucose (PPG), glucagon and insulin levels. METHODS: Six randomized, placebo-controlled studies of lixisenatide 20 µg once daily were included in this analysis: lixisenatide as monotherapy (GetGoal-Mono), as add-on to oral antidiabetic drugs (OADs; GetGoal-M, GetGoal-S) or in combination with basal insulin (GetGoal-L, GetGoal-Duo-1 and GetGoal-L-Asia). Change in 2-h PPG and glucose excursion were evaluated across six studies. Change in 2-h glucagon and postprandial insulin were evaluated across two studies. A meta-analysis was performed on least square (LS) mean estimates obtained from analysis of covariance (ANCOVA)-based linear regression. RESULTS: Lixisenatide significantly reduced 2-h PPG from baseline (LS mean difference vs. placebo: -4.9 mmol/l, p < 0.001) and glucose excursion (LS mean difference vs. placebo: -4.5 mmol/l, p < 0.001). As measured in two studies, lixisenatide also reduced postprandial glucagon (LS mean difference vs. placebo: -19.0 ng/l, p < 0.001) and insulin (LS mean difference vs. placebo: -64.8 pmol/l, p < 0.001). There was a stronger correlation between 2-h postprandial glucagon and 2-h PPG with lixisenatide than with placebo. CONCLUSIONS: Lixisenatide significantly reduced 2-h PPG and glucose excursion together with a marked reduction in postprandial glucagon and insulin; thus, lixisenatide appears to have biological effects on blood glucose that are independent of increased insulin secretion. These effects may be, in part, attributed to reduced glucagon secretion.

Engineering spatial gradients of signaling proteins using magnetic nanoparticles.

Intracellular biochemical reactions are often localized in space and time, inducing gradients of enzymatic activity that may play decisive roles in determining cell's fate and functions. However, the techniques available to examine such enzymatic gradients of activity remain limited. Here, we propose a new method to engineer a spatial gradient of signaling protein concentration within Xenopus egg extracts using superparamagnetic nanoparticles. We show that, upon the application of a magnetic field, a concentration gradient of nanoparticles with a tunable length extension is established within confined egg extracts. We then conjugate the nanoparticles to RanGTP, a small G-protein controlling microtubule assembly. We found that the generation of an artificial gradient of Ran-nanoparticles modifies the spatial positioning of microtubule assemblies. Furthermore, the spatial control of the level of Ran concentration allows us to correlate the local fold increase in Ran-nanoparticle concentration with the spatial positioning of the microtubule-asters. Our assay provides a bottom-up approach to examine the minimum ingredients generating polarization and symmetry breaking within cells. More generally, these results show how magnetic nanoparticles and magnetogenetic tools can be used to control the spatiotemporal dynamics of signaling pathways.

Impact of wave front and coherence optimization in coherent diffractive imaging.

We present single shot nanoscale imaging using a table-top femtosecond soft X-ray laser harmonic source at a wavelength of 32 nm. We show that the phase retrieval process in coherent diffractive imaging critically depends on beam quality. Coherence and image fidelity are measured from single-shot coherent diffraction patterns of isolated nano-patterned slits. Impact of flux, wave front and coherence of the soft X-ray beam on the phase retrieval process and the image quality are discussed. After beam improvements, a final image reconstruction is presented with a spatial resolution of 78 nm (half period) in a single 20 fs laser harmonic shot.

Design strategies of hybrid metallic nanoparticles for theragnostic applications.

Metallic nanoparticles (MNPs) such as iron oxide and gold nanoparticles are interesting platforms to build theragnostic nanocarriers which combine both therapeutic and diagnostic functions within a single nanostructure. Nevertheless, their surface must be functionalized to be suitable for in vivo applications. Surface functionalization also provides binding sites for targeting ligands, and for drug loading. This review focuses on the materials and surface chemistry used to build hybrid nanocarriers that are inorganic cores functionalized with organic materials. The surface state of the MNPs largely depends on their synthesis routes, and dictates the strategies used for functionalization. Two main strategies can be found in the literature: the design of core-shell nanosystems, or embedding nanoparticles in organic materials. Emerging tendencies such as the use of clusters or alternative coating materials are also described. To present both hydrophilic and lipophilic nanosystems, we chose the doxorubicin anticancer agent as an example, as the molecule presents an affinity for both types of materials.

A low membrane lipid phase transition temperature is associated with a high cryotolerance of Lactobacillus delbrueckii subspecies bulgaricus CFL1.

The mechanisms of cellular damage that lactic acid bacteria incur during freeze-thaw processes have not been elucidated to date. Fourier transform infrared spectroscopy was used to investigate in situ the lipid phase transition behavior of the membrane of Lactobacillus delbrueckii ssp. bulgaricus CFL1 cells during the freeze-thaw process. Our objective was to relate the lipid membrane behavior to membrane integrity losses during freezing and to cell-freezing resistance. Cells were produced by using 2 different culture media: de Man, Rogosa, and Sharpe (MRS) broth (complex medium) or mild whey-based medium (minimal medium commonly used in the dairy industry), to obtain different membrane lipid compositions corresponding to different recovery rates of cell viability and functionality after freezing. The lipid membrane behavior studied by Fourier transform infrared spectroscopy was found to be different according to the cell lipid composition and cryotolerance. Freeze-resistant cells, exhibiting a higher content of unsaturated and cyclic fatty acids, presented a lower lipid phase transition temperature (Ts) during freezing (Ts=-8°C), occurring within the same temperature range as the ice nucleation, than freeze-sensitive cells (Ts=+22°C). A subzero value of lipid phase transition allowed the maintenance of the cell membrane in a relatively fluid state during freezing, thus facilitating water flux from the cell and the concomitant volume reduction following ice formation in the extracellular medium. In addition, the lipid phase transition of freeze-resistant cells occurred within a short temperature range, which could be ascribed to a reduced number of fatty acids, representing more than 80% of the total. This short lipid phase transition could be associated with a limited phenomenon of lateral phase separation and membrane permeabilization. This work highlights that membrane phase transitions occurring during freeze-thawing play a fundamental role in the cryotolerance of Lb. delbrueckii ssp. bulgaricus CFL1 cells.

[Place of the flexible ureterorenoscopy first choice for the treatment of kidney stones. Survey results practice committee of the AFU lithiasis completed in 2011]. / Place de l'urétérorénoscopie souple en première intention pour le traitement des calculs du rein. Résultats de l'enquête de pratique du comité lithiase de l'AFU réalisée en 2011.

UNLABELLED: The flexible ureterorenoscopy coupled with photovaporisation LASER (USSR-L) for the treatment of kidney kidney is a modern tool whose place is under evaluation. METHODS: Its place has been assessed in France in 2010 by the Committee of urolithiasis of the French Association of Urology (CLAFU). A practice survey among 27 experts concerned the following decision criteria: comorbid patient's supposed nature of the calculation, anatomy of the urinary tract of the patient. This investigation has been proposed to calculate the size not exceeding 20mm, for a calculation of size greater than 20mm and for multiple calculations kidney. RESULTS: Fourteen experts responded. The criteria for the USSR-The first line were: morbid obesity (BMI>30), anticoagulation or anti platelet aggregation, calculations Hard (UH>1000, cystine stones), calculations within diverticular caliceal calculations below, the failure of a first treatment or the wish of the patient. CONCLUSION: The URS-SL was a first-line treatment validated regardless of size and number of kidney stones, when ESWL and PCNL were contraindicated or when their predictable results were poor (hard stones/morbid obesity/lower pole stones) or when stone access is difficult (intradiverticular). It was also the treatment of choice after the failure of a first treatment (ESWL/PCNL).

[Management of adult's renal and ureteral stones. Update of the Lithiasis Committee of the French Association of Urology (CLAFU). General considerations]. / Prise en charge urologique des calculs rénaux et urétéraux de l'adulte. Mise au point du Comité Lithiase de l'Association Française d'Urologie (CLAFU). Aspects généraux.

The Lithiasis Committee of the French Association of Urology (CLAFU) aimed to update the current knowledge about urolithiasis. This update will be divided into four parts: 1) general considerations; 2) the management of ureteral stones; 3) the management of kidney stones; 4) metabolic assessment and medical treatment of urolithiasis. Recent technicals advances helped the urologists to improve stones management: new extracorporeal shockwave lithotripsy (ESWL) devices, new flexible ureterorenoscopes, development of laser fragmentation. ESWL, semi-rigid and flexible ureteroscopy and the percutaneous nephrolithotomy (PCNL) remain currently the main therapeutic options. The first part of this update deals with the description and classification of stones, preoperative assessment, post-operative management and clinical follow-up. Main criteria of therapeutic choices are stone location, stone composition and stone size. Stone composition is assessed with infrared spectrophotometry analysis and its hardness is correlated with U.H. density on CT scan assessment. Preoperative assessment consists in urinary cytobacteriological examine, urinary PH, blood creatininemia, hemostasis. Low-dose CT scan is recommended before urological treatment. The result of the treatment must be done 1 or 3 months later with plain abdominal film and ultrasonography. Medical management of urolithiasis will be based on stone composition, metabolic and nutritional evaluation. Treatment success is definited by absence of residual fragments. Annual follow-up is recommended and based either on plain abdominal film and ultrasonography or low-dose CT scan.

Zinc transporter (ZnT)8(186-194) is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients.

AIMS/HYPOTHESIS: Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets. METHODS: Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-γ enzyme-linked immunospot. RESULTS: White HLA-A2(+) adults (83%) and children (60%) with type 1 diabetes displayed ZnT8-reactive CD8(+) T cells that recognised a single ZnT8(186-194) (VAANIVLTV) epitope. This ZnT8(186-194)-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8(+) T cells. Another sequence, ZnT8(153-161) (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8(186-194), 0% for ZnT8(153-161)). CONCLUSIONS/INTERPRETATION: ZnT8-reactive CD8(+) T cells are predominantly directed against the ZnT8(186-194) epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8(186-194) may point to common environmental triggers precipitating beta cell autoimmunity.

Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling.

Adipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.