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Group 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (T H 2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings. ILC2 metabolism has been largely unexplored. Di Santo and colleagues examine metabolic profiles from naive and cytokine-activated ILC2s and find that IL-33-triggered ILC2s rely on distinct metabolic pathways to sustain proliferation and function.

Innate lymphoid cells (ILCs) include cytotoxic natural killer cells and distinct groups of cytokine-producing innate helper cells which participate in immune defense and promote tissue homeostasis. Circulating human ILC precursors (ILCP) able to generate all canonical ILC subsets via multi-potent or uni-potent intermediates according to our previous work. Here we show potential cooperative roles for the Notch and IL-23 signaling pathways for human ILC differentiation from blood ILCP using single cell cloning analyses and validate these findings in patient samples with rare genetic deficiencies in IL12RB1 and RORC . Mechanistically, Notch signaling promotes upregulation of the transcription factor RORC , enabling acquisition of Group 1 (IFN-γ) and Group 3 (IL-17A, IL-22) effector functions in multi-potent and uni-potent ILCP. Interfering with RORC or signaling through its target IL-23R compromises ILC3 effector functions but also generally suppresses ILC production from multi-potent ILCP. Our results identify a Notch->RORC- > IL-23R pathway which operates during human ILC differentiation. These observations may help guide protocols to expand functional ILC subsets in vitro with an aim towards novel ILC therapies for human disease. Innate lymphoid cells (ILC) are effector cells that rapidly respond to immune evading stimuli, and despite their functional diversity arise from common precursors. Authors here show how the Notch signalling pathway orchestrates ILC development from circulating human ILC precursors via RORC and its target IL-23R.

The quality control testing of chemical degradations in the bio-pharmaceutical industry is currently under controversial debate. Here we have systematically applied in vitro and in vivo stress conditions to investigate the influence of protein degradation on structure-function. Extensive purification and characterization enabled identification and functional assessment of the physiological degradation of chemical modification sites in the variable complementarity-determining regions (CDRs) and conserved region of trastuzumab. We demonstrate that the degradation of the solvent-accessible residues located in the CDR and the conserved fragment crystallizable region (Fc) occurs faster in vivo (within days) compared to the levels observed for bio-process and real-time storage conditions. These results hence question the rationality of extreme monitoring of low level alterations in such chemical modifications as critical patient safety parameters in product quality control testing, given that these modifications merely mirror the natural/physiological aging process of endogenous antibodies. Ingrid Schmid and colleagues identified and evaluated the physiological degradation of chemical modification sites of trastuzumab. This study suggests that in vitro PBS incubation studies can be used to predict the protein degradation sites in vivo for critical quality attribute assessment.

BackgroundAlthough NSAIDs and COX2 inhibitors show clinical promise, their toxicities limit their cancer therapeutic use. PGE2 is a metabolite from the COX2 pathway, well known to mediate immunosuppressive functions through EP2 and EP4 receptors and downstream cAMP signaling in immune cells, which suppresses their anti-tumoral activities. Similarly, PGD2, a metabolite of HPGDS, known to bind DP1, has recently been proposed to play pro-tumoral functions. OKN4395 is a novel small molecule, highly selective and potent against EP2, EP4, and DP1, intended to block the pro-tumor activities of PGE2 and PGD2, while avoiding other prostanoid receptors to reduce side effects.MethodsOKN4395’s efficacy and selectivity were rigorously characterized in a series of vitro and vivo preclinical assays. Given that the biology of DP1 is not fully understood, we confirmed using primary immune cell that its signaling was similar to the one of EP2/EP4 and further evaluated the redundancy of PGD2 with PGE2 in vitro. In addition, combination potential with anti-PD1 was evaluated.ResultsA comprehensive selectivity screen confirmed that OKN4395 selectively inhibits EP2, EP4, and DP1 receptors, with no off-target effects on other prostanoid receptors. In vitro, OKN4395 exhibited robust potency in counteracting the immunosuppressive effects of PGE2 and PGD2 in human T cells and NK cells. Our data demonstrated that PGE2 and PGD2 can fully compensate for each other’s effects; notably, the blockade of EP2, EP4, and DP1 receptors was able to effectively restore NK and CD8+ T cell anti-tumor functions when both PGE2 and PGD2 were present at high concentrations. In a mixed lymphocyte reaction assay, we showed that the well-characterized activity of anti-PD1 on IFN-γ secretion was fully blocked by prostaglandins and could only be rescued by the activity of OKN4395. Furthermore, the potent anti-tumor effect of OKN4395 in combination with anti-PD1 was demonstrated using an in vitro killing assay. In vivo, OKN4395 significantly reduced tumor growth as a monotherapy and demonstrated instances of complete tumor regression when combined with anti-PD1. Finally, pharmacokinetic and tolerability profiles from non-clinical studies supported further clinical development.ConclusionsOur studies demonstrate that triple inhibition of EP2, EP4, and DP1 with OKN4395 is more effective than dual EP2/EP4 inhibition in restoring anti-tumor immune responses in presence of both PGE2 and PGD2. These compelling results strongly endorse the clinical development of OKN4395, currently in a Phase 1 trial (NCT06789172), as a novel immunotherapy for solid tumors, both as a standalone treatment and in combination with anti-PD1.Ethics ApprovalAll human derived material used in the study were obtained under ethics and regulatory approvals.

Methylation of cytosines is a prototypic epigenetic modification of the DNA. It has been implicated in various regulatory mechanisms across the animal kingdom and particularly in vertebrates. We mapped DNA methylation in 580 animal species (535 vertebrates, 45 invertebrates), resulting in 2443 genome-scale DNA methylation profiles of multiple organs. Bioinformatic analysis of this large dataset quantified the association of DNA methylation with the underlying genomic DNA sequence throughout vertebrate evolution. We observed a broadly conserved link with two major transitions—once in the first vertebrates and again with the emergence of reptiles. Cross-species comparisons focusing on individual organs supported a deeply conserved association of DNA methylation with tissue type, and cross-mapping analysis of DNA methylation at gene promoters revealed evolutionary changes for orthologous genes. In summary, this study establishes a large resource of vertebrate and invertebrate DNA methylomes, it showcases the power of reference-free epigenome analysis in species for which no reference genomes are available, and it contributes an epigenetic perspective to the study of vertebrate evolution. DNA methylation is involved in regulatory processes throughout the animal kingdom. Here, the authors map DNA methylation in 535 vertebrates and 45 invertebrates, establishing a reference dataset for cross-species analysis and exploring epigenetic variation across vertebrate evolution.

The Angler Saddleback pig is an endangered local breed originating from Germany. The breed is said to have low demands in terms of husbandry and feeding, and an excellent meat quality. To date, there is a lack of more recent scientific investigations of the breed. Therefore, 58 Angler Saddleback pigs were fattened in two consecutive trials whereby performance, carcass quality and meat quality were assessed. At an average age of 324 days, the pigs reached an average final live weight of 143 kg, an intramuscular fat (IMF) content of 2.6%, a lean meat percentage of 47% and a backfat thickness of 38 mm. A significant influence of the independent variables “breeder” and “age at the end of fattening” on the majority of target variables was found. Furthermore, IMF as well as pH value 45 minutes post mortem was significantly influenced by sex. These results give a current overview of the phenotypic characteristics of this endangered breed. It is shown that the slower growing Angler Saddleback breed may need alternative marketing concepts for its meat and meat products. Additionally, further research is necessary to clarify the reasons for the high phenotypic variation within this breed.

Purpose This paper aims to explore the manoeuvring room of higher education institutions to take action to reduce emissions from academic flying. In particular, this study investigates how university staff and central actors in university management evaluate potential measures in this area. Design/methodology/approach The authors applied a single case study design encompassing an online survey directed at staff (N = 338) and 11 semi-structured interviews with key actors from management at an Austrian university. The authors used descriptive statistics and qualitative content analysis to examine the data. Findings This study found considerable support among university staff in principle for implementing measures to reduce academic flying, but also serious concerns about the fairness and viability of some restrictive measures, especially disincentives and caps on flying. However, bans on short-haul flights were largely supported. Actors from university management saw their manoeuvring room limited by the potential resistance and non-compliance of staff, as well as by framework conditions external to the university. Practical implications Dedicated leadership is needed to facilitate broad commitment within the university and to avoid shifting the responsibility between different governance levels. Restrictive measures to reduce academic air travel will be more readily accepted if perceived as fair and viable. Originality/value Although several papers have addressed the behavioural and institutional factors that sustain extensive flying in academia, to the best of the authors’ knowledge, this is one of the first contributions to investigate the potentials and challenges of introducing measures to reduce air travel in higher education institutions.

Background Local cattle breeds need special attention, as they are valuable reservoirs of genetic diversity. Appropriate breeding decisions and adequate genomic management of numerically smaller populations are required for their conservation. At this point, the analysis of dense genome-wide marker arrays provides encompassing insights into the genomic constitution of livestock populations. We have analyzed the genetic characterization of ten cattle breeds originating from Germany, The Netherlands and Denmark belonging to the group of red dairy breeds in Northern Europe. The results are intended to provide initial evidence on whether joint genomic breeding strategies of these populations will be successful. Results Traditional Danish Red and Groningen White-Headed were the most genetically differentiated breeds and their populations showed the highest levels of inbreeding. In contrast, close genetic relationships and shared ancestry were observed for the populations of German Red and White Dual-Purpose, Dutch Meuse-Rhine-Yssel, and Dutch Deep Red breeds, reflecting their common histories. A considerable amount of gene flow from Red Holstein to German Angler and to German Red and White Dual-Purpose was revealed, which is consistent with frequent crossbreeding to improve productivity of these local breeds. In Red Holstein, marked genomic signatures of selection were reported on chromosome 18, suggesting directed selection for important breeding goal traits. Furthermore, tests for signatures of selection between Red Holstein, Red and White Dual-Purpose, and Meuse-Rhine-Yssel uncovered signals for all investigated pairs of populations. The corresponding genomic regions, which were putatively under different selection pressures, harboured various genes which are associated with traits such as milk and beef production, mastitis and female fertility. Conclusions This study provides comprehensive knowledge on the genetic constitution and genomic connectedness of divergent red cattle populations in Northern Europe. The results will help to design and optimize breeding strategies. A joint genomic evaluation including some of the breeds studied here seems feasible.