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Adrenocortical carcinomas (ACC) are aggressive and resistant to medical treatment. This study reports a single-nucleus transcriptome atlas of steroid and microenvironment cells in 38 human normal adrenals and adrenocortical tumors. We identify intermediate-state cells between glomerulosa and fasciculata, a transition state in the centripetal trans-differentiation of normal steroid cells. In tumors, steroid cells show expression programs reflecting this zonation. Although ACC microenvironment is scarce, its signatures combine with those of steroid cells into ecotypes. A first ecotype combines cancer-associated fibroblasts, tumor-associated endothelial cells, with hypoxia and mitosis signatures in steroid cells. Another ecotype combines exhausted T cells, with fasciculata steroid signature. These ecotypes are associated with poor survival. Conversely, a third ecotype combines inflammatory macrophages, with reticularis steroid signature, and better outcome. These steroid/microenvironment cells interplays improve outcome predictions and may open therapeutic options in aggressive ACC, through immune microenvironment activation by modulating glucocorticoids/androgens balance. Adrenocortical carcinomas (ACC) are aggressive and often resistant to therapy. Here, the authors provide a single-nucleus transcriptomic atlas of ACCs and normal adrenal glands, finding ecotypes in steroid and microenvironment cells that are associated with clinical outcomes.

Locomotor exercise may induce corticospinal excitability and/or cortical inhibition change in the knee extensors. This study investigated whether the mode of muscle contraction involved during a locomotor exercise modulates corticospinal and intracortical responsiveness. Eleven subjects performed two 45-min treadmill walking exercises in an uphill (+ 15%) or a downhill (− 15%) condition matched for speed. Maximal voluntary isometric torque (MVIC), voluntary activation level (VAL), doublet (Dt) twitch torque, and M-wave area of the knee extensors were assessed before and after exercise. At the same time-points, motor-evoked potential (MEP), cortical silent period (CSP), and short-interval cortical inhibition (SICI) were recorded in the vastus lateralis (VL) and rectus femoris (RF) muscles. After exercise, uphill and downhill conditions induced a similar loss in MVIC torque (− 9%; p < 0.001), reduction in VAL (− 7%; p < 0.001), and in M-wave area in the VL muscle (− 8%; p < 0.001). Dt twitch torque decreased only after the downhill exercise (− 11%; p < 0.001). MEP area of the VL muscle increased after the downhill condition (p = 0.007), with no change after the uphill condition. MEP area of the RF muscle remained stable after exercises. CSP and SICI did not change in the two conditions for both muscles. Downhill walking induces an increase in MEP area of the VL muscle, with no change of the CSP duration or SICI ratio. The eccentric mode of muscle contraction during a locomotor exercise can modulate specifically corticospinal excitability in the knee extensors.

The functional structures of communities respond to environmental changes by both species replacement (turnover) and within-species variation (intraspecific trait variability; ITV). Evidence is lacking on the relative importance of these two components, particularly in response to both short- and long-term environmental disturbance. We hypothesized that such short- and long-term perturbations would induce changes in community functional structure primarily via ITV and turnover, respectively. To test this we applied an experimental design across long-term mown and abandoned meadows, with each plot containing a further level of short-term management treatments: mowing, grazing and abandonment. Within each plot, species composition and trait values [height, shoot biomass, and specific leaf area (SLA)] were recorded on up to five individuals per species. Positive covariations between the contribution of species turnover and ITV occurred for height and shoot biomass in response to both short- and long-term management, indicating that species turnover and intraspecific adjustments selected for similar trait values. Positive covariations also occurred for SLA, but only in response to long-term management. The contributions of turnover and ITV changed depending on both the trait and management trajectory. As expected, communities responded to short-term disturbances mostly through changes in intraspecific trait variability, particularly for height and biomass. Interestingly, for SLA they responded to long-term disturbances by both species turnover and intraspecific adjustments. These findings highlight the importance of both ITV and species turnover in adjusting grassland functional trait response to environmental perturbation, and show that the response is trait specific and affected by disturbance regime history.

Breccias associated with tectonic, fluid and sedimentary evolution of rifted margins can provide information on a variety of processes reflecting the modes of extension. In this paper, we analyse the numerous breccias exposed in the Agly Massif that was part of the European side of the Cretaceous rift now inverted in the eastern Pyrenees. Using a combination of petrologic and sedimentologic analyses, field-based structural study, and multivariate analysis of clast shape and diversity, binding lithology and size, and breccia fabrics, we distinguish 5 types of breccias reflecting depositional, tectonic, and salt-related processes. The integration of these processes in the tectonic history of the eastern Pyrenees confirms the attribution of these breccias to the Cretaceous rifting. We emphasize the major role played by the evaporitic Triassic particularly during the first stages of rifting as a major decoupling level at the basement/cover interface. Salt tectonics and shearing assisted by the circulation of fluids are reflected by hydrofracturing at the base of the Mesozoic cover. As this weak mechanical layer is later extracted as extension increases, a brittle detachment system developed along the cover-basement interface to exhume of deep crust and mantle. The relationships between brecciation and Cretaceous extension in the Pyrenees argue for a mixed mode of rifting associated with ductile and brittle deformation during the formation of the hyper-extended rift domain. Les brèches associées à l’évolution tectonique, sédimentaire et fluide des systèmes de rifts sont des marqueurs d’une variété de processus qui reflètent les modes d’extension. Dans ce papier, nous présentons une analyse des différentes brèches du Massif de l’Agly qui appartient à la partie européenne du rift crétacé inversé dans les Pyrénées Orientales. Cette étude pluridisciplinaire combine des données sédimentologiques, pétrologiques, structurales ainsi qu’une analyse statistique intégrant les formes et diversité des clastes, les lithologies et granulométrie du liant et la fabrique des brèches. Nous distinguons 5 types de brèches qui reflètent des processus sédimentaires et tectoniques, et la remobilisation des niveaux évaporitiques. L’intégration de ces processus dans l’histoire tectonique des Pyrénées Orientales confirme la formation de ces différentes brèches durant l’épisode de rifting crétacé. Nous mettons ainsi en évidence le rôle majeur des évaporites du Trias qui jouent le rôle de niveau de décollement aux interfaces socle/couverture durant les phases précoces du rifting. La tectonique salifère et le cisaillement sur ces interfaces socle/couverture, assistés par les circulations fluides sont exprimés par les nombreuses évidences de fracturation hydraulique à la base de la couverture mésozoïque. Avec l’augmentation de l’extension, ce niveau faible mécaniquement est extrait, entraînant la formation d’un système de détachement à comportement fragile. L’évolution de ce détachement préférentiellement localisé au niveau des interfaces socle/couverture, conduit à l’exhumation de la croûte profonde et du manteau. Les relations entre les processus de formation des brèches et l’extension crétacée mettent en évidence un mode de rifting dominé par un régime mixte à la fois cassante et ductile au cours de la formation des domaines hyper-étirées du rift pyrénéen.

Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck. This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18–75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0–3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1–14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov, NCT02022098, and is still active but not recruiting. Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6–29·4) in the Debio 1143 group and 24·2 months (6·6–26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39–69) of 48 patients in the Debio 1143 group versus 16 (33%; 20–48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13–6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3–4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group. To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients. Debiopharm.

Considering both within‐ and between‐species functional diversities in plant communities has been recently suggested as a way to understand potential assembly mechanisms that control species coexistence. In particular, relating variations in species richness to within‐ and between‐species functional diversities can provide a useful framework for evaluating the importance of alternative community assembly theories. In addition, little is known about whether the relationship between species richness and functional diversity components arises from direct or indirect effects of the abiotic environment. We tested the relationship between functional diversity and species richness by disentangling functional diversity components into within‐species, between‐species and total functional diversities and by considering potential direct and indirect effects of the abiotic conditions. Multi‐ and single‐trait approaches were applied using three key plant functional traits (height, specific leaf area (SLA), LDMC). Traits were measured on species coexisting across sixteen species‐rich limestone grasslands. Direct and indirect effects of the abiotic conditions were evaluated using multiple soil properties including heterogeneity in soil depths. The within‐species functional diversity ranged between 13.5% and 33.6% of the total functional diversity. Within‐species diversity was the main functional component linked to variations in species richness, despite the within‐species functional diversity being lower than between‐species functional diversity. Environmental soil properties had a direct effect on species richness but did not affect functional diversity components. Synthesis: Our results provide evidence that increasing the trait overlap between species, due to an increase in within‐species diversity, may relate to greater species coexistence. Disentangling multiple functional diversity components indicated that there may be equalizing mechanisms that act as potential drivers of species coexistence. In addition, it suggests the possibility that this approach may provide a better understanding of the processes involved in the structure of plant communities.

Digital therapeutics (DTx) represent a transformative shift in health care delivery, offering software-driven, evidence-based therapeutic interventions. Despite their potential, adoption remains low across health care systems, partly due to insufficient economic evidence. Significant knowledge gaps persist regarding stakeholders' approaches to economic decisions in DTx development, with prior studies also indicating limited consideration of economic factors in early DTx development stages, particularly from researchers. This study investigates how researchers approach decision-making regarding factors that influence the economic impact of DTx during technological development and clinical validation phases, examining the underlying mechanisms and contextual conditions that shape these processes. Using a critical realism philosophical stance, 17 semistructured interviews were conducted with researchers involved in DTx development, including research engineers (n=5), health systems and social science researchers (n=6), clinician-researchers (n=4), and practitioner-researchers (n=2). The research approach combined deductive and inductive coding, followed by abductive and retroductive inference processes to identify generative mechanisms underlying observed decision-making patterns. Qualitative system dynamics modeling was applied to visualize causal loop relationships through triangulated data sources. Three interrelated generative mechanisms were identified that shape researchers' decision-making regarding economic considerations: (1) the professional norms, operating through reinforcing loops that systematically prioritize clinical validation while marginalizing economic considerations; (2) the researcher experience, revealing how professional training and limited economic literacy create cognitive biases that obscure economic factors; and (3) the DTx adoption uncertainties, demonstrating how implementation concerns influence development decisions through both reinforcing and balancing feedback loop dynamics. These mechanisms explain why, despite growing recognition of the importance of economic evidence, economic considerations remain peripheral in researchers' decision frameworks. This study reveals complex interactions between institutional structures, intrapersonal factors, and implementation uncertainties that systematically deprioritize economic considerations in DTx development. The identified mechanisms provide valuable intervention points for strengthening the development process toward a more comprehensive assessment of clinical, technical, and economic value throughout the DTx lifecycle to ultimately enhance their adoption in health care systems.

PurposeTo examine corticospinal excitability and neuromuscular function following the completion of eccentric (ECC) or concentric (CON) maximal exercises of same mechanical work.MethodsTen males (29.9 ± 11.8 years) performed maximal isokinetic knee extensor contractions in four experimental sessions. The two first sessions (one in ECC and one in CON) ended with a dynamic peak torque loss of 20%. The work completed in each contraction type was then achieved in the other contraction type. Neuromuscular function- maximal voluntary isometric contraction (MVIC), voluntary activation level (VAL), potentiated doublet (Dt), M-wave- and corticospinal excitability- motor evoked potential (MEP) amplitude and silent period (SP)—were assessed in the vastus lateralis (VL) and rectus femoris (RF) muscles at 20% MVIC before and immediately after exercise.ResultsTo lose 20% of dynamic peak torque subjects performed 1.8 times more work in ECC than CON (P = 0.03), inducing a non-different decline in MVIC (P = 0.15). VAL dropped after the ECC sessions only (− 8.5 ± 6.7%; all P < 0.027). Only, the CON session featuring the greatest work affected Dt amplitude (− 9.4 ± 23.8%; P = 0.047). In both muscles, MEP amplitude decreased (all P < 0.001) and MEP SP stayed constant (all P > 0.45), irrespective of contraction type (all P > 0.15).ConclusionSame-work maximal ECC and CON exercises induced similar fatigue level but from different origins (preferentially central for ECC vs peripheral for CON). Yet, net corticospinal excitability did not depend on contraction type.

Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcγ receptors (FcγR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo . Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone loss. The IgG sugar moiety modulates the binding of immune complexes to their Fcγ receptors resulting in pro- or anti-inflammatory response. This study shows that IgG sialylation also affects osteoclastogenesis and bone mass in mice and humans, identifying a new link between bone and the immune system.

Shifts in insect distributions have been reported globally, largely attributed to climate and landscape changes. Communities are being reshaped, with species response traits mediating the effects of changing environments. Using a machine-learning approach we model 1252 insect occupancies across three decades in Great Britain. We combine independent models of nine insect groups (butterflies, moths, odonates, orthopterans, carabids, ladybirds, bees, wasps and hoverflies) to take a high-level view of the trends and key environmental drivers of insect occupancy, as well as to highlight the trait mediations underlying the resulting niches. Across this wide taxonomic range, we identify common trends in insect occupancies, showing no Great Britain-wide decline since 1990, but instead local declines and changes in community compositions. Known drivers of biodiversity loss appear to underlie those changes, notably urban sprawl and landscape simplification. Our approach also highlights the crucial roles of two response traits: habitat breadth, in mediating the effects of changing landscapes diversity and voltinism, in mediating the effects of increasing temperatures on insect life cycles. The authors identify changes in insect distribution across Great Britain since 1990. The changes appear connected to insect traits, notably with species with multiple generations per year benefiting from increasing temperatures, particularly in the North.