Cryogenic testing of the integrated Ariel space telescope: design of the optical test equipment

In this proceeding, we present the development of the Optical Ground Support Equipment (OGSE) used for payload-level testing of the Ariel space mission. Ariel is an ESA mission that will use the transit spectroscopy method to observe the atmospheres of nominally ~1000 exoplanets. Ariel is a 1 m class cryogenic (∼ 40 K) space telescope that will be placed in a halo orbit around the Earth-Sun L2 point. To detect atmospheric molecular absorption features, Ariel will produce medium-resolution spectra (R ≥ 15) using three spectroscopic channels covering 1.1 – 7.9 μm as well as having photometric channels covering 0.5 – 1.1 μm. To achieve Ariel’s science goals, the payload requires detailed calibration and performance verification. The payload-level performance verification of the Ariel payload will take place in 2026 in a 5-meter vacuum chamber at the Rutherford Appleton Laboratory’s Space Instruments Test Facility. The payload will be enclosed in a Cryogenic Test Rig (CTR) to provide a space-like (~35 K) thermal environment and is illuminated by the OGSE. The OGSE provides point as well as extended source illumination across Ariel’s full wavelength range. The OGSE design also includes a series of mechanisms and features to enable the various illumination conditions required to test Ariel. Here we report design updates to the OGSE after a preliminary design review (PDR). Since PDR, there have been substantial revisions to the OGSE architecture. In this proceeding, we describe the evolution of the OGSE architecture. The updated OGSE design will then be presented

Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors

Molecular Biomarkers for Weight Control in Obese Individuals Subjected to a Multiphase Dietary Intervention

Context: Although calorie restriction has proven beneficial for weight loss, long-term weight control is variable between individuals.Objective: To identify biomarkers of successful weight control during a dietary intervention (DI).Design, Setting, and Participants: Adipose tissue (AT) transcriptomes were compared between 21 obese individuals who either maintained weight loss or regained weight during the DI. Results were validated on 310 individuals from the same study using quantitative reverse transcription polymerase chain reaction and protein levels of potential circulating biomarkers measured by enzyme-linked immunosorbent assay.Intervention: Individuals underwent 8 weeks of low-calorie diet, then 6 months of ad libitum diet.Outcome Measure: Weight changes at the end of the DI.Results: We evaluated six genes that had altered expression during DI, encode secreted proteins, and have not previously been implicated in weight control (EGFL6, FSTL3, CRYAB, TNMD, SPARC, IGFBP3), as well as genes for which baseline expression differed between those with good and poor weight control (ASPN, USP53). Changes in plasma concentrations of EGFL6, FSTL3, and CRYAB mirrored AT messenger RNA expression; all decreased during DI in individuals with good weight control. ASPN and USP53 had higher baseline expression in individuals who went on to have good weight control. Expression quantitative trait loci analysis found polymorphisms associated with expression levels of USP53 in AT. A regulatory network was identified in which transforming growth factor β1 (TGF-β1) was responsible for downregulation of certain genes during DI in good controllers. Interestingly, ASPN is a TGF-β1 inhibitor.Conclusions: We found circulating biomarkers associated with weight control that could influence weight management strategies and genes that may be prognostic for successful weight control

Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis.

International audienceAdipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4

Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.

When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity

Fasting plasma parameters in 12-wk wild type (WT) and HSL^+/− HFD-fed mice and in 12-wk wild type HFD-fed mice treated with vehicle or HSL specific inhibitor (HSLi) for 7 consecutive days.

<p>Values (<i>n</i> = 6–17) are means ± SEM. NEFA, nonesterified fatty acid; QUICKI, quantitative insulin sensitivity check index; RBP4, retinol binding protein 4.</p

Glucose metabolism and insulin sensitivity in mice with reduced HSL activity.

<p>(A) In vivo 2-deoxy-D-[³H] glucose uptake under stimulation by insulin in skeletal muscle (<i>biceps femoris</i>—BF—and <i>soleus</i>) and WAT. (B) Ex vivo glucose oxidation in <i>soleus</i> muscle. (C) Respiratory quotient assessed by indirect calorimetry and expressed as percentage of cumulative relative frequencies (PCRF). EC₅₀ are represented by arrows. (D) In vivo insulin bolus. Variation in plasma glucose 15 min after injection of saline or insulin (a.u., arbitrary unit). (E) Effect of insulin bolus in vivo on hepatic insulin signalling. IRS1, insulin receptor substrate 1; Akt, protein kinase B. (F) Hepatic de novo lipogenesis. Measurement of radiolabelled glucose incorporation in lipid fraction of liver after insulin stimulation. (G) Pyruvate tolerance test. (H) Liver glycogen content assessed in mice starved for 24 h and then refed for 18 h. Values are means ± SEM. WT mice (▪ or ▴) and HSL^+/− mice (□) mice (<i>n</i> = 4–10 in each group). * <i>p</i><0.05, ** <i>p</i><0.01 versus WT mice.</p

Relationship between WAT lipolysis and de novo lipogenesis.

<p>(A) Up-regulation of glucose transporter 4 and de novo lipogenesis-related pathways. Induction of gene expression (red boxes) in hMADS adipocytes with HSL gene silencing were determined by DNA microarray analysis and validated by reverse transcription-quantitative PCR (indicated by *). (B) Up-regulation of glucose transporter 4 and de novo lipogenesis-related pathway gene expression in hMADS adipocytes. mRNA levels were determined by reverse transcription-quantitative PCR (<i>n</i> = 9–12). ** <i>p</i><0.01 versus siGFP. (C) Correlations between glucose transporter 4, carbohydrate responsive element-binding protein, and fatty acid synthase mRNA levels and, lipolysis in human WAT (<i>n</i> = 45). (D) Up-regulation of glucose transporter 4 and de novo lipogenesis-related pathway gene expression in adipocytes from obese individuals treated with placebo or nicotinic acid (<i>n</i> = 12 per group). * <i>p</i><0.05, ** <i>p</i><0.01 versus before treatment. ACC, acetylCoA carboxylase; ACL, ATP citrate lyase; ACS, acetyl-CoA synthase; ChREBP, carbohydrate responsive element-binding protein; DCT, dicarboxylate transporter; FAE, fatty acid elongase; FAS, fatty acid synthase; GPDH, glycerol-3-phosphate dehydrogenase; GLUT4, glucose transporter 4; G6PDH, glucose-6-phosphate dehydrogenase; LDH, lactate dehydrogenase; MDH, malate dehydrogenase; ME, malic enzyme; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PK, pyruvate kinase; SCD, stearoylCoA desaturase.</p