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Abstract Central serous chorioretinopathy (CSCR) is a retinal disease characterised by the accumulation of subretinal fluid, which often resolves spontaneously in acute cases. However, approximately one-third of patients experience recurrences that may cause severe and irreversible vision. This study aimed to identify parameters derived from optical coherence tomography (OCT) that are associated with CSCR recurrence. Our dataset included 5211 OCT scans from 344 eyes of 255 patients diagnosed with CSCR. 178 eyes were identified as recurrent, 109 as non-recurrent, and 57 were excluded. We extracted parameters using artificial intelligence algorithms based on U-Nets, convolutional kernels, and morphological operators. We applied inferential statistics to evaluate differences between the recurrent and non-recurrent groups, and we used a logistic regression predictive model, reporting the coefficients as a measure of biomarker importance. We identified nine predictive biomarkers for CSCR recurrence: age, intraretinal fluid, subretinal fluid, pigment epithelial detachments, choroidal vascularity index, integrity of photoreceptors and retinal pigment epithelium layer, choriocapillaris and choroidal stroma thickness, and thinning of the outer nuclear layer, and of the inner nuclear layer combined with the outer plexiform layer. These results could enable future developments in the automatic detection of CSCR recurrence, paving the way for translational medical applications.

Acts of abuse are indicative of a parent's inability to regulate his or her own emotions in an appropriate manner and jeopardize a child's development. Foster care should provide a safe environment both to protect a child from harm and to heal a damaging social-emotional developmental trajectory. How does a child learn to regulate his or her emotions faced with the two different environments of foster home and parental home? This study is based on the use of a microanalytic observation method using a video-recording device in natural settings. It concerns a preschooler, Lola, aged 5, and her birth parents and Foster Mother (FM), who together form her caregivers. To evaluate the evolution of their interactions over a year, three observational sessions were held at an interval of six months. The emotional regulation learning processes used by Lola and her caregivers during playtime were analyzed with Emotion Regulation Strategies (ERS) coding systems in order to build ERS cycles. The analysis of this case showed that Lola learnt to develop language strategies to regulate her emotions with her FM, while exhibiting self-soothing behaviors and distraction strategies with her biological parents. The degree of distress and emotional tension in her birth family had a critical impact on Lola's ERS learning processes. Clinical implications for child care practices are discussed following a clinical psychology perspective.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values

Abstract Cholinergic striatal interneurons (ChIs) express the vesicular glutamate transporter 3 (VGLUT3) which allows them to regulate the striatal network with glutamate and acetylcholine (ACh). In addition, VGLUT3-dependent glutamate increases ACh vesicular stores through vesicular synergy. A missense polymorphism, VGLUT3-p.T8I, was identified in patients with substance use disorders (SUDs) and eating disorders (EDs). A mouse line was generated to understand the neurochemical and behavioral impact of the p.T8I variant. In VGLUT3T8I/T8I male mice, glutamate signaling was unchanged but vesicular synergy and ACh release were blunted. Mutant male mice exhibited a reduced DA release in the dorsomedial striatum but not in the dorsolateral striatum, facilitating habit formation and exacerbating maladaptive use of drug or food. Increasing ACh tone with donepezil reversed the self-starvation phenotype observed in VGLUT3T8I/T8I male mice. Our study suggests that unbalanced dopaminergic transmission in the dorsal striatum could be a common mechanism between SUDs and EDs.

Summary: Background: In industrialized countries, the incidence of inflammatory bowel disease (IBD) appears stabilized. This study examined the incidence and phenotype of IBD in Northern France over a 30-year period. Methods: Including all IBD patients recorded in the EPIMAD population-based registry from 1988 to 2017 in Northern France, we described the incidence and clinical presentation of IBD according to age, sex and time. Findings: A total of 22,879 incident IBD cases were documented (59% (n = 13,445) of Crohn’s disease (CD), 38% (n = 8803) of ulcerative colitis (UC), 3% (n = 631) of IBD unclassified (IBDU)). Over the study period, incidence of IBD, CD and UC was 12.7, 7.2 and 5.1 per 105 person-years, respectively. The incidence of CD increased from 5.1/105 in 1988–1990 to 7.9/105 in 2015–2017 (annual percent change (APC): +1.9%, p

Abstract Restoring ecological dynamics is a key objective of conservation translocations. Exemplarily, reconnecting the reintroduced alpine populations with native Pyrenean populations through re‐establishing locally extinct populations in between, in the Causses and the Pre‐Alps, is a major goal for the long‐term conservation of Bearded Vultures in Europe. Understanding Bearded Vultures' post‐release movements and foraging behavior is critical to understanding the settlement of newly restored populations and to supporting conservation measures. The telemetric monitoring of 43 translocated and wild‐born juveniles allowed us to investigate whether differences exist in post‐release movements and foraging behavior during the first year of life between reintroduced and native populations. Medium‐ and long‐distance exploration movements start during the spring following fledging for both translocated and wild‐born individuals. However, birds translocated in the most distant release site (Causses) exhibited greater exploration distances with no clear directional movement pattern, had smaller home ranges, and had a stronger preference for supplementary feeding stations than those from other populations. Although some birds translocated in the Pre‐Alps displayed similar behaviors, the pattern is not as strong as in the Causses, likely because of the proximity to the breeding populations reintroduced in the Alps or differences in the number and management of supplementary feeding stations. Preference for supplementary feeding stations (SFS) mostly occurred in the Pre‐Alps and the native populations, but was lower in the Causses. Seasonal variations in SFS preference were consistent among populations, with a peak in the first spring following fledging. Beyond documenting post‐release movements in Bearded Vultures, we suggest better accounting for the demographic consequences of behaviors to track conservation translocation effectiveness, at both local and regional scales.

Effective conservation management of wildlife species depends on understanding their space and habitat use. Telemetry has become the primary source of data for information on how species use space and habitats. However, animals can be difficult to capture, leading to limited sample sizes and thus low quality inferences. As some individuals may be easier to capture than others, it may be tempting to use them to make inferences about the studied population as a whole. Juvenile birds, in contrast to adults, are easy to capture while they are still in the nest. However, there are few studies on when and how they might serve to obtain a representative characterization of the habitat or space use of adults. This study investigated this by using GPS‐tracking data of 35 adult/juvenile dyads of golden eagles Aquila chrysaetos, with the juvenile and adult in a dyad sharing the same home‐range. We assessed juvenile‐to‐adult home‐range overlap and also compared their relative use of habitats within that space. We also analysed how these metrics evolved throughout the post‐fledging dependence period (PFDP). During this period, juvenile‐to‐adult similarity was more than 80% for the entire home‐range, whereas it was lower for the core area (approximately 60%). Habitat‐use similarity was high, at approximately 90% for both the home‐range and core area, both in land‐cover and topography. The similarity increased following the improvement of juvenile flight skills over a period of two months, to the extent that two months after fledging and until the end of the PFDP, habitat and space use of juveniles can be used to infer the home‐range and habitat requirements of adults. It would be valuable to study this ‘adult‐by‐juvenile replacement' approach in other species to determine whether it could be generalized, notably for species with a shorter dependence period or more complex social interactions.

Background Anorexia nervosa (AN) is a severe psychiatric disorder associated with frequent relapses and variability in treatment responses. Previous literature suggested that such variability is influenced by premorbid vulnerabilities such as abnormalities of the reward system. Several factors may indicate these vulnerabilities, such as neurocognitive markers (tendency to favour delayed reward, poor cognitive flexibility, abnormal decision process), genetic and epigenetic markers, biological and hormonal markers, and physiological markers.The present study will aim to identify markers that can predict body mass index (BMI) stability 6 months after discharge. The secondary aim of this study will be focused on characterising the biological, genetic, epigenetic and neurocognitive markers of remission in AN.Methods and analysis One hundred and twenty-five (n=125) female adult inpatients diagnosed with AN will be recruited and evaluated at three different times: at the beginning of hospitalisation, when discharged and 6 months later. Depending on the BMI at the third visit, patients will be split into two groups: stable remission (BMI≥18.5 kg/m²) or unstable remission (BMI

In a recent paper, Farfán et al. (2023) suggested that a population of griffon vultures in Málaga province (southern Spain) have gradually become habituated to the presence of wind turbines, and even actively avoid them, thus reducing the risk of collision. We believe, however, that their general conclusion that vultures have left the study area of impact immediately after construction of the windfarm, and have gradually recolonized the area, while avoiding collisions by passing alongside or above the wind turbines, is not supported by the results presented. Below we raise three key points explaining why the conclusions of Farfán et al. (2023) are flawed.

BackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.MethodsA secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (

Introduction Anorexia nervosa (AN) is a severe and chronic psychiatric disorder, resulting from a voluntary food restriction, vomiting, use of laxatives and excessive exercises, leading in dramatic weight loss and high mortality. AN is a multifactorial disease involving genetic and epigenetic factors supporting that AN is a metabo-psychiatric disorder. The molecular mechanisms involved in the etiology of AN remain unclear. One work reported gene expression by RNA sequencing in peripheral blood before and after weight restoration in 6 AN patients (Kim 2013), and one RNA sequencing in human iiPSC-derived neurons from 4 patients and 4 controls (Negraes 2017). To date, the profile of expression of genes and proteins in AN is undetermined. Objectives In this study, our goal is to identify specific gene expression signatures from circulating blood nuclear cells to decipher the pathophysiology of AN and characterize biomarkers that can be used for diagnostic or prognostic of AN. Methods All consented participants are recruited at Sainte-Anne Hospital, Paris, France, using DSM5 criteria. They had a blood draw in Paxgene tube for the collection of RNAs. Total RNA was extracted from peripheral blood mononuclear cells of 15 patients suffering of AN and 15 healthy controls. All messenger RNAs are sequenced on a Novaseq plateform. Reads are aligned to the human genome 19 and statistical analyses on the read counts for differentially expressed genes are computed with DESeq2. Results The total RNA sequencing allows us to identify 673 dysregulates genes (p adjusted value 1,5). Among them, 248 are down-regulated and 425 are up-regulated genes in AN patients compared to controls. From them, 151 transcripts are annotated as pseudogene and 45 are referenced as antisense RNA. Of the 522 remaining transcripts, 424 correspond to a transcript or protein annotated by HGNC and ENSEMBL and 93 are known pseudogenes. A large number of proteins resulting from the expression of deregulated genes interact with each other and form a statistically enriched network impacting biological processes. They are mainly increased and acting in the cellular machinery allowing protein synthesis (biological process: transcription, ribosome, spliceosome and mitochondria). In contrast, down-regulated genes present an enrichment in genes involved in immunity pathways. Finally, several genes are also expressed in the brain. We observed a significant enrichment of genes expressed in the blood and brain tissues. Conclusions We identify specific profiles of gene expression in AN. Several genes are both blood and brain tissue expression. Some genes are good candidates for biomarker of the diagnostic in AN that need to be investigated in a longitudinal study to evaluate their useful as prognostic biomarker of AN. This work is supported by Fondation de France & Fédération Recherche sur le Cerveau. Disclosure of Interest None Declared

Abstract Purpose The present study aimed to explore the implicit associations between food and bodily stimuli in patients with anorexia nervosa (AN) and control subjects (HC). Methods A Go/No-Go Association Task was administrated to 55 participants (28 AN and 27 HC), using food stimuli (low-calorie food vs. high-calorie food) and body stimuli (underweight vs. overweight bodies). Results We evidenced an implicit association between food and body stimuli in the AN group, whereas the HC group only showed a tendency. AN and HC groups also exhibited different categorization strategies: the AN group tended to categorize stimuli as low-calorie foods and underweight bodies less than the HC group, and they tended to categorize stimuli as high-calorie foods and overweight bodies more than the HC group. Conclusion The present study revealed for the first time specificities of the AN population’s implicit association between food and body stimuli in terms of association strength and categorization strategy. Furthermore, the results suggest that combining implicit methodologies with other methods could contribute to a better characterization of the physiopathology of AN. Level of evidence Level I, experimental study.

BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Abstract Multidisciplinary Design Optimization (MDO) enables one to reach a better solution than by optimizing each discipline independently. In particular, the optimal structure of a drone varies depending on the selected material. The $$CO_2$$ C O 2 footprint of a solar-powered High Altitude Long Endurance (HALE) drone is optimized here, where the structural materials used is one of the design variables. Optimization is performed using a modified version of OpenAeroStruct, a framework based on OpenMDAO. Our EcoHale framework is validated on a classical HALE testcase in the MDO community (FBhale) constructed using high-fidelity codes compared to our low-fidelity approach. The originality of our work is to include two specific disciplines (energy and environment) to adapt to a new problem of $$CO_2$$ C O 2 minimization. The choice of eco-materials is performed in the global MDO loop from a choice of discrete materials . This is achieved through a variable relaxation, enabling the use of continuous optimization algorithms inspired from multimaterial topology optimization. Our results show that, in our specific case of electric drone, the optimal material in terms of $$CO_2$$ C O 2 footprint is also the optimal material in terms of weight. It opens the door to new researches on digital microarchitectured materials that will decrease the $$CO_2$$ C O 2 footprint of the drone.

Abstract Background Bio-logging devices play a fundamental and indispensable role in movement ecology studies, particularly in the wild. However, researchers are aware of the influence that attaching devices can have on animals, particularly on their behaviour, energy expenditure and survival. The way a device is attached to an animal’s body has also potential consequences for the collected data, and quantifying the type and magnitude of such potential effects is fundamental to enable researchers to combine and compare data from different studies, as much as it is to improve animal welfare. For over two decades, large terrestrial birds have been in the focus of long-term movement ecology research, employing bio-logging devices attached with different types of harnesses. However, comparative studies investigating the effects of different harness types used on these species are scarce. Methods In this study, we tested for potential differences in data collected by two commonly used harness types, backpack and leg-loop, on the flight performance of 10 individuals from five soaring raptor species, equipped with high resolution bio-logging devices, in the same area and time. We explored the effect of harness type on vertical speed, airspeed, glide ratio, height above sea level, distance travelled, proportion of soaring and flapping behaviour, and VeDBA (a proxy for energy expenditure) between and within individuals, all used as fine-scale measures of flight performance. Results Birds equipped with leg-loops climbed up to 0.36 ms $$^{-1}$$ - 1 faster, reached 25.9% greater altitudes while soaring and spent less time in active flight compared to birds equipped with backpacks, suggesting that backpack harnesses, compared to leg-loops, might cause additional drag affecting the birds’ flight performance. A lower VeDBA, a lower rate of sinking while gliding and slightly higher glide ratio and airspeeds were also indicative of less drag using leg-loops, even though the effect on these parameters was comparable to inter-individual differences. Conclusions Our results add to the existing literature highlighting the design-related advantages of leg-loops, and support the use of leg-loops as a better alternative to backpack harnesses for large soaring birds, when possible. Our study also highlights how apparently small changes in device attachment can lead to notable improvements in tagging practice, with implications for animal welfare, data interpretation and comparability.

ContextThe use of vagus nerve stimulation (VNS) to reduce or stop electroconvulsive therapy (ECT) in treatment-resistant depression seems promising. The aim of this study was to investigate the efficacy of VNS on the reduction of ECT sessions and mood stabilization.MethodsWe conducted a monocentric retrospective case series of patients who suffered from treatment-resistant depression, treated with ECT and referred to our center for VNS. We investigated the number and the frequency of ECT sessions before and after VNS implantation. Secondary criteria consisted in the Montgomery Åsberg Depression Rating Scale (MADRS) score, number of medical treatments, dosage of the main treatment and length of hospital stays before and after VNS. Additionally, we sent an anonymous survey to psychiatrists and other physicians in our institution to investigate their knowledge and perception of VNS therapy to treat treatment-resistant depression.ResultsSeven patients benefited from VNS: six (86%) were female (mean age of 51.7 +/− 16.0 years at surgery), and five (71%) suffered from bipolar depression (three type I and two type II). All patients were followed up at least 2 years post-implantation (range: 27–68 months). Prior to VNS, six patients were treated by maintenance ECT. After VNS, three (43%) patients did not require maintenance ECT anymore, and three (43%) patients required less frequent ECT session with a mean 14.7 +/− 9.8 weeks between sessions after VNS vs. 2.9 +/− 0.8 weeks before VNS. At last follow-up, 4 (57%) patients had stopped ECT. Five (71%) patients implanted with VNS were good responders (50% decrease relative to baseline MADRS). According to the survey, psychiatrists had a significantly better perception and knowledge of ECT, but a worse perception and knowledge of VNS compared to other physicians.ConclusionVNS is a good option for treatment-resistant depression requiring maintenance ECT dependence. Larger on-going studies will help broaden the implanted patients while strengthening psychiatrists’ knowledge on this therapy.

BackgroundBorderline personality disorder is often associated with self-injurious behaviors that cause personal suffering, family distress, and substantial medical costs. Mental health hotlines exist in many countries and have been shown to be effective in some contexts, but none have been specifically designed for borderline patients. The aim of the present study is to evaluate the impact of a 24/7 hotline dedicated to patients with borderline personality disorder on suicide attempts and self-injurious behaviors.MethodsWe conducted a single-blind, multicenter (9 French centers) clinical trial with stratified randomization (by age, sex and center). Patients (N = 315) with a diagnosis of borderline personality disorder (according to the SIDP-IV) were randomized into two groups with or without access to the hotline in addition to treatment as usual. The number of suicide attempts and self-injurious behaviors in each group within 12 month were analyzed in the “per protocol” population (Student’s t-tests, 5% significance threshold), adjusting for possible confounders in a multivariate analysis (using Poisson regression). The percentage of patients with suicide attempts and with self-injurious behaviors (and other percentages) were analyzed in the per protocol population (χ2-tests or exact Fischer tests, 5% significance threshold).ResultsThe mean number of suicide attempts was 3 times lower in the hotline group (0.41 vs. 1.18, p = 0.005) and the mean number of self-injurious behaviors was 9 times lower (0.90 vs. 9.5, p = 0.006). Multivariate analysis confirmed the effectiveness of the hotline in reducing suicide attempts and self-harm.ConclusionThis study supports the effectiveness of hotlines in reducing self-aggressive behavior in patients with borderline personality disorder. Such support is easy to use, cheap and flexible, and therefore easy to implement on a large scale.

El objetivo de esta investigación fue comprender la consistencia de los discursos y prácticas evaluativas de las autoridades universitarias y personal docente de la carrera de Ingeniería de Sistemas de la Universidad Nacional de Ingeniería (UNI) durante el 2012-2017. Este estudio se desarrolló bajo el paradigma cualitativo y el punto de vista del Interaccionismo Simbólico. Se aplicó el enfoque metodológico del estudio de caso intrínseco. Las entrevistas y el análisis de contenido fueron los métodos utilizados y en correspondencia se eligieron las entrevistas individuales semiestructuradas y el análisis documental como técnicas. Se seleccionaron dieciocho informantes claves, entre docentes y autoridades que cumplían los criterios comunes definidos y los no comunes según sea el caso. Con base en las teorías de la evaluación de los aprendizajes, se estudiaron los discursos institucionales y orales de los informantes. Como resultado principal se evidencia que en la carrera de Ingeniería de Sistemas prevalecen las técnicas de desempeño, destacando el uso de exámenes o pruebas objetivas, proyectos de curso y tareas de curso como instrumentos evaluativos. Existe correspondencia entre el discurso escrito institucional desde el Reglamento de Régimen Académico (RRA) de la Universidad y las prácticas evaluativas del personal docente. Existe coherencia entre el discurso oral y escrito sobre la evaluación de los aprendizajes en la carrera en estudio, el cual se inclina hacia una perspectiva evaluativa conductista. La evaluación de los aprendizajes en la carrera y, por ende, en la universidad es aplicada de acuerdo con el modelo conductista, a través de técnicas e instrumentos que permiten la comprobación del conocimiento adquirido por el estudiantado. El aporte principal es a la evaluación educativa, a la evaluación de los aprendizajes, con una Propuesta para implementar la coherencia entre el discurso y la práctica evaluativa en la UNI y en la carrera Ingeniería de Sistemas.

This paper presents a laboratory investigation of the strain-dependent cyclic properties of a compacted tropical residual soil as measured in a resonant column and cyclic triaxial testing program. The mechanical properties were evaluated with respect to cyclic shear strain amplitude, initial void ratio, and confining pressure. It was shown that the existing models for the prediction of shear modulus reduction and damping ratio curves were not pertinent in the case of the compacted residual soil studied. Empirical equations were developed for the small-strain shear modulus and the normalized shear modulus, damping ratio, and pore water pressure ratio curves for void ratios between e = 1.00 and e = 1.50 and mean effective pressures of p′ = 50−300 kPa. The comparison of the models to the measured values suggest that the uncertainties associated with each of these models are lower than 20% of the predicted values. The results were established as part of a project for the construction of an embankment dam in the West Indies. However, the methodology as well as the model formulation framework presented in the article can be generalized to other residual soils and applied in all fields of geotechnical engineering.

Summary: LEAP-2 is a ghrelin antagonist with an anorexigenic drive. This study investigates the evolution of plasma ghrelin and LEAP-2 concentrations in 29 patients with anorexia nervosa (AN) before and after refeeding and compares it to physiological adaptations during fasting in healthy controls or to mouse model of chronic food restriction and refeeding. Acute and chronic food restriction decrease LEAP-2 and increase ghrelin concentrations in both humans and mice, while patients with AN displayed higher ghrelin and LEAP-2 concentrations before than after refeeding (p = 0.043). After 6 months follow-up, patients with unstable weight gain (n = 17) had significantly decreased LEAP-2 concentrations after refeeding (p = 0.044), in contrast to patients with stable weight gain (n = 12). We provide evidence that the ghrelin/LEAP-2 system is not regulated according to the nutritional status in AN, in contrast to what is physiologically expected when coping with food restriction.

IntroductionT cell expressed CD27 provides costimulation upon binding to inducible membrane expressed trimeric CD70 and is required for protective CD8 T cell responses. CD27 agonists could therefore be used to bolster cellular vaccines and anti-tumour immune responses. To date, clinical development of CD27 agonists has focussed on anti-CD27 antibodies with little attention given to alternative approaches.MethodsHere, we describe the generation and activity of soluble variants of CD70 that form either trimeric (t) or dimer-of-trimer proteins and conduct side-by-side comparisons with an agonist anti-CD27 antibody. To generate a dimer-of-trimer protein (dt), we fused three extracellular domains of CD70 to the Fc domain of mouse IgG1 in a ‘string of beads’ configuration (dtCD70-Fc).ResultsWhereas tCD70 failed to costimulate CD8 T cells, both dtCD70-Fc and an agonist anti-CD27 antibody were capable of enhancing T cell proliferation in vitro. Initial studies demonstrated that dtCD70-Fc was less efficacious than anti-CD27 in boosting a CD8 T cell vaccine response in vivo, concomitant with rapid clearance of dtCD70-Fc from the circulation. The accelerated plasma clearance of dtCD70-Fc was not due to the lack of neonatal Fc receptor binding but was dependent on the large population of oligomannose type glycosylation. Enzymatic treatment to reduce the oligomannose-type glycans in dtCD70-Fc improved its half-life and significantly enhanced its T cell stimulatory activity in vivo surpassing that of anti-CD27 antibody. We also show that whereas the ability of the anti-CD27 to boost a vaccine response was abolished in Fc gamma receptor (FcγR)-deficient mice, dtCD70-Fc remained active. By comparing the activity of dtCD70-Fc with a variant (dtCD70-Fc(D265A)) that lacks binding to FcγRs, we unexpectedly found that FcγR binding to dtCD70-Fc was required for maximal boosting of a CD8 T cell response in vivo. Interestingly, both dtCD70-Fc and dtCD70-Fc(D265A) were effective in prolonging the survival of mice harbouring BCL1 B cell lymphoma, demonstrating that a substantial part of the stimulatory activity of dtCD70-Fc in this setting is retained in the absence of FcγR interaction.DiscussionThese data reveal that TNFRSF ligands can be generated with a tunable activity profile and suggest that this class of immune agonists could have broad applications in immunotherapy.