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Lentic waters are biogeochemical reactors, producing and receiving carbon (C) originally fixed by the terrestrial and aquatic biosphere, which is then buried in sediments or respired back to the atmosphere in the forms of carbon dioxide (CO2) and one of the more potent greenhouse gas (GHG) methane (CH4). Additionally, lakes serve as archives of terrestrial and aquatic carbon processes within their sediments, enabling the reconstruction of historical changes spanning thousands of years. These changes encompass alterations in land cover, indicated by pollen records, soil carbon erosion and shifts in lake productivity resulting from changes in land use and climate. Both the burial of C in lakes and the emissions of GHGs are recognised as important components of Earth's climate system, yet they remain poorly understood and constrained due to inadequate quantities and qualities of observations. In the case of GHG emissions from lakes, observations are often sporadic, failing to capture the significant spatial and temporal variations in emissions across diverse lentic systems. To address this challenge, process-based models that incorporate the interconnected biogeochemical processes occurring within lakes and their watersheds would arguably be the best tool to extrapolate from site-level observations to regional and finally global scales, to quantify the anthropogenic impact on these fluxes and to reconstruct long-term shifts in emissions and burial due to changes in land cover and climate. However, the development and evaluation of such models is hampered by the lack of observations in sufficient quality. In this project, we bring together a unique consortium of specialists in aquatic ecology, biogeochemistry, palynology, sedimentology and modelling of terrestrial and aquatic biogeochemistry. This project will put forth a national programme of systematic, long-term observations of lake GHG and C cycling processes of unmet detail, consistency and quality. First, at 40 pilot sites spanning typological and environmental gradients, there will be a comprehensive data acquisition endeavour to evaluate biological processes and mesological factors influencing the sequestration or recycling of organic carbon. This effort will be complemented with a synthesis of existing data (WP1). Second, based on well-dated sediment records, which include both newly-acquired and synthesised existing data, variability of lake C burial and their climate and land-use controls will be reconstructed over the past 150 years (WP2). For 15 of these pilot sites, reconstruction will go back until the mid-Holocene (5,000 years BP), allowing us to shed light on the anthropogenic perturbation of the C cycle in this earlier part of human history, which is commonly excluded from this type of research due to lack of information. The activities of these first two WPs will result in an open-source national database, guaranteeing valorisation of our research far beyond this project. In WP3, we will use the land surface model (LSM) ORCHIDEE C-lateral to assess C cycling in the terrestrial biosphere and the mobilisation of biospheric C into lakes, which is possible due to an explicit representation of soil C leaching and erosion processes and a downscaling scheme permitting us to assess C exports from watersheds at sub-grid scale. While LSMs are used to assess evolution of biospheric C budgets from the beginning of the Industrial Period, we will use it to hindcast the evolution since the mid-Holocene, using lake sediment records for model validation. Moreover, we will develop a new process-based lake C model supported by the database established in WPs 1 and 2, which we will couple to ORCHIDEE C-lateral to simulate lake C burial and GHG emissions in response to climate and processes in the lake watershed. This model set-up will first be used to better constrain contemporary large-scale lake GHG emissions and to disentangle the anthropogenic perturbation of these fluxes from the natural background flux. These estimates will be revolutionary, as they will allow attributing part of lake GHG emissions to anthropogenic emissions for national GHG budget reporting. Then, these models will be emulated to reconstruct evolution of lake GHG budgets and C budgets of the whole lake watershed since the mid-Holocene. While simulations will first be performed at the scales of France and Europe, the development of international partnerships to implement observations from other biomes (WP4) will finally support simulations at the global scale.

Metformin and IACS‐010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS‐010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS‐01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS‐01075.

Abstract Background Prostate cancer (PCa) ranks as the second most prevalent cancer in men, with advanced stages posing significant treatment challenges. Given its solid tumor nature, PCa is highly susceptible to hypoxia, a condition associated with resistance to radiation and chemotherapy, metastasis, and unfavorable patient outcomes. Hypoxia-inducible factors (HIFs) play a pivotal role in cancer cell adaptation to hypoxic environments, contributing to treatment resistance. Consequently, inhibitors targeting HIFs hold promise for cancer therapy. Methods In this study, we aimed to characterize novel HIF-1α inhibitors including Sodwanones A (1), B (2), C (3), G (4) and Yardenone 2 (5) isolated from marine sponges belonging to the Axinella genus. Our investigation evaluated the impact of these compounds on various aspects of HIF-1α regulation, including stabilization, nuclear localization, expression of HIF-1 target genes (while sparing HIF-2 target genes), cellular metabolism, as well as cell proliferation and viability in prostate cells under hypoxic conditions. Results Our findings revealed that among the compounds tested, Yardenone 2 exhibited notable effects in hypoxia: it destabilized HIF-1α at the protein level, decreased its nuclear localization, selectively altered the expression of HIF-1 target genes, and restrained cell proliferation in aggressive PC3 prostate cancer cells as well as in an MSK-PCa3 patient-derived organoid line. Moreover, it affected the morphology of these organoid. Yardenone 2 was also compared to Docetaxel, a specific microtubule inhibitor and a drug used in the treatment of prostate cancer. The comparison between the two compounds revealed notable differences, such as a lack of specificity to hypoxic cells of Docetaxel. Conclusion These results mark the first demonstration that Yardenone 2 functions as a cytostatic-like inhibitor impacting microtubules, specifically targeting hypoxic cancer cells. This discovery suggests a promising avenue for novel therapeutic interventions in prostate cancer.

Abstract Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2’s transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

Background Approximately 50% of women referred for invasive coronary angiography have angina and nonobstructive coronary arteries, which includes coronary microvascular dysfunction, vasospastic angina, and other vasomotor disorders. We sought to determine the real‐world diagnostic yield of invasive coronary angiography and coronary function testing in women with angina and nonobstructive coronary arteries. Methods and Results From 2018 to 2023, we enrolled 198 women who underwent either coronary angiography (CA) alone (n=99) or coronary function testing (CFT; n=99). Mean±SD age was 62±10 years (CA alone) compared with 57±10 years (CFT). Coronary angiography was interpreted as nonobstructive coronary artery disease more frequently after CA alone (79% versus 52%). Of the women who underwent CFT, 82% (N=81) were found to have vasomotor disorders, including coronary microvascular dysfunction (27%), vasospastic angina (32%), mixed coronary microvascular dysfunction/vasospastic angina (16%), endothelial dysfunction (10%; without spasm), elevated resting flow (2%), or symptomatic myocardial bridging (4%). Compared with women undergoing CA alone, medications were changed more frequently after CFT at 24 hours (41% versus 65%; P=0.001) and between 24 hours and 30 days (30% versus 44%; P=0.04) with intensification of antianginal therapy (79% versus 92%; P80% of women undergoing CFT received a specific diagnosis of a coronary vasomotor disorder and greater intensification of antianginal therapy.

The urgency to reach net-zero emissions until 2050 has created a vast interest in innovative technologies for renewable energy sector. At the same time the need for trusty and unfailing solutions will rise considering the increasing amount of decentralized and decarbonized energy systems. It has previously been described in the literature that the aforementioned characteristics could be combined by blockchain technology. Therefore, this study focuses on the practical side – the opinion of industry experts about the use of blockchain in renewable energy. By using SWOT, PESTLE and analytic hierarchy process analysis, the goal of this study is to develop a methodology for the selection of the most appropriate blockchain applications in renewable energy and to identify and evaluate the possible types of use considering socio-economic, political and legal, technological and environmental factors. The results of this study highlight the important influence of political, legal and technological factors like involvement of government institutions and possible attacks to the system, but considers the economic factors as the least significant for the introduction and use of blockchain technology in the renewable energy sector. The most promising use cases for blockchain would be associated with reliable and immutable certificates of origin for renewable energy and use in smart grid (including smart metering), smart homes and relevant Internet of Things applications. The use of crypto-assets and initial coin offerings for renewable energy development should be viewed with precaution and willingness to inform and educate considering social factors like public opinion and societies’ knowledge on crypto-assets.

Abstract Medulloblastoma is a cancerous brain tumor that affects mostly children. Among the four groups defined by molecular characteristics, Group 3, the least well characterized, is also the least favorable, with a survival rate of 50%. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not adequate and the lack of understanding of the different molecular features of Group 3 tumor cells makes the development of effective therapies challenging. In this study, the problem of medulloblastoma is approached from a metabolic standpoint in a low oxygen microenvironment. We establish that Group 3 cells use both the mitochondrial glycerol-3 phosphate (G3PS) and malate-aspartate shuttles (MAS) to produce NADH. Small molecules that target G3PS and MAS show a greater ability to decrease cell proliferation and induce apoptosis specifically of Group 3 cells. In addition, as Group 3 cells show improved respiration in hypoxia, the use of Phenformin, a mitochondrial complex 1 inhibitor, alone or in combination, induced significant cell death. Furthermore, inhibition of the cytosolic NAD+ recycling enzyme lactate dehydrogenase A (LDHA), enhanced the effects of the NADH shuttle inhibitors. In a 3D model using Group 3 human cerebellar organoids, tumor cells also underwent apoptosis upon treatment with NADH shuttle inhibitors. Our study demonstrates metabolic heterogeneity depending on oxygen concentrations and provides potential therapeutic solutions for patients in Group 3 whose tumors are the most aggressive.

Abstract Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome‐wide CRISPR‐Cas9 knockout screen, which revealed the LKB1‐SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria‐targeted antioxidant promotes enhanced cell death efficacy in LKB1‐ and SIK2‐negative uveal melanoma cells compared to control cells. Our study also identified an LKB1‐loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.

Total Knee Arthroplasty has well-established success in relieving knee pain and improving function but patients do not reach functional levels of control groups after surgery and 20% of patients remain unsatisfied. To understand the different patient profiles and develop patient-specific approaches of care, functional phenotypes based on knee biomechanics during gait have been evaluated. To widen the understanding of patient's function, it seems crucial to consider the gait devieations at the whole body level. Thus, this study aims at 1) assessing the impact of knee OA on full-body gait mechanics, 2) assessing whether potential deviations persist one year after TKA surgery, and 3) their potential impact on satisfaction. To that end, clinical gait analysis was performed before and one year after surgery for 100 patients planned for unilateral primary TKA, along with 32 healthy participants as control group. Patients were clustered by applying K-means algorithms on full-body kinematic features of gait before surgery. The knee was excluded from classification to focus on full-body kinematics. Differences between groups, with controls, as well as before and after surgery were evaluated for patients reported outcome measures, kinematic features, and spatio-temporal parameters. Three functional groups were identified. One low-functioning cluster with mostly elderly women showing significant functional improvement one year after surgery, and two high-functioning clusters differentiated by pelvis tilt (anteversion vs. retroversion), sagittal knee alignment (varus vs. neutral), and knee flexion during stance phase (flexum vs. extended) that showed limited improvement one year after surgery. Satisfaction rates were similar among clusters and mental scores improved for all clusters. High functioning patients may benefit from TKA, mostly due to pain reduction, but may not see significant improvement of their function, with no clear impact on satisfaction rate. On the contrary, patients with important functional limitation are more likely to improve both pain and functional outcomes.

Long-term effects of climate change on lakes globally will include a substantial modification in the thermal regime and the oxygen solubility of lakes, resulting in the alteration of ecosystem processes, habitats, and concentrations of critical substances. Recent efforts have led to the development of long-term model projections of climate change effects on lake thermal regimes and oxygen solubility. However, such projections are hardly ever confronted with observations extending over multiple decades. Furthermore, global-scale forcing parameters in lake models present several limitations, such as the need of significant downscaling. In this study, the effects of climate change on thermal regime and oxygen solubility were analyzed in the four largest French peri-alpine lakes over 1850–2100. We tested several one-dimensional (1D) lake models' robustness for long-term variations based on up to 63 years of limnological data collected by the French Observatory of LAkes (OLA). Here, we evaluate the possibility of forcing mechanistic models by following the long-term evolution of shortwave radiation and air temperature while providing realistic seasonal trends for the other variables for which local-scale downscaling often lacks accuracy. Based on this approach, MyLake, forced by air temperatures and shortwave radiations, predicted accurately the variations in the lake thermal regime over the last 4 to 6 decades, with RMSE < 1.95 ∘C. Over the previous 3 decades, water temperatures have increased by 0.46 ∘C per decade (±0.02 ∘C) in the epilimnion and 0.33 ∘C per decade (±0.06 ∘C) in the hypolimnion. Concomitantly and due to thermal change, O2 solubility has decreased by −0.104 mg L−1 per decade (±0.005 mg L−1) and −0.096 mg L−1 per decade (±0.011 mg L−1) in the epilimnion and hypolimnion, respectively. Based on the shared socio-economic pathway SSP370 of the Intergovernmental Panel on Climate Change (IPCC), peri-alpine lakes could face an increase of 3.80 ∘C (±0.20 ∘C) in the next 70 years, accompanied by a decline of 1.0 mg L−1 (±0.1 mg L−1) of O2 solubility. Together, these results highlight a critical alteration in lake thermal and oxygen conditions in the coming decades, and a need for a better integration of long-term lake observatories data and lake models to anticipate climate effects on lake thermal regimes and habitats.

IntroductionThree-dimensional gait analysis is widely used for the clinical assessment of movement disorders. However, measurement error reduces the reliability of kinematic data and consequently assessment of gait deviations. The identification of high variability is associated with low reliability and those parameters should be ignored or excluded from gait data interpretation. Moreover, marker placement error has been demonstrated to be the biggest source of variability in gait analysis and may be affected by factors intrinsic to the evaluators such as the evaluator's expertise which could be appraised through his/her experience and confidence in marker placement.ObjectivesIn the present study, we hypothesized that confidence in marker placement is correlated with kinematic variability and could potentially be used as part of a score of reliability. Therefore, we have proposed a questionnaire to evaluate qualitatively the confidence of evaluators in lower-limb marker placement. The primary aim of this study was to evaluate the reliability and validity of the presented questionnaire. The secondary objective was to test a possible relationship between marker placement confidence and kinematics variability.MethodsTo do so, test-retest gait data were acquired from two different experimental protocols. One protocol included data from a cohort of 32 pathological and 24 asymptomatic subjects where gait analysis was repeated three times, involving two evaluators. A second protocol included data from a cohort of 8 asymptomatic adults with gait analysis repeated 12 times, per participant, and involving four evaluators with a wider range of experience.ResultsResults demonstrated that the questionnaire proposed is valid and reliable to evaluate qualitatively the confidence of evaluators in placing markers. Indeed, confidence scores were correlated with the actual variability of marker placement and revealed the evaluator's experience and the subjects' characteristics. However, no correlation was observed between confidence scores and kinematic variability and the formulated hypothesis was not supported.

The primary cilium, a non‐motile organelle present in most human cells, plays a crucial role in detecting microenvironmental changes and regulating intracellular signaling. Its dysfunction is linked to various diseases, including cancer. We explored the role of ciliated cells in prostate cancer by using Gefitinib and Jasplakinolide compounds to induce ciliated cells in both normal and tumor‐like prostate cell lines. We assessed GLI1 and IFT20 expression and investigated YAP1 protein's role, which is implicated in primary cilium regulation. Finally, we examined these compounds in 3D cell models, aiming to simulate in vivo conditions. Our study highlights YAP1 as a potential target for novel genetic models to understand the primary cilium's role in mediating resistance to anticancer treatments. [ABSTRACT FROM AUTHOR]

Total Knee Arthroplasty has well-established success in relieving knee pain and improving function but patients do not reach functional levels of control groups after surgery and 20% of patients remain unsatisfied. To understand the different patient profiles and develop patient-specific approaches of care, functional phenotypes based on knee biomechanics during gait have been evaluated. To widen the understanding of patient's function, it seems crucial to consider the gait devieations at the whole body level. Thus, this study aims at 1) assessing the impact of knee OA on full-body gait mechanics, 2) assessing whether potential deviations persist one year after TKA surgery, and 3) their potential impact on satisfaction. To that end, clinical gait analysis was performed before and one year after surgery for 100 patients planned for unilateral primary TKA, along with 32 healthy participants as control group. Patients were clustered by applying K-means algorithms on full-body kinematic features of gait before surgery. The knee was excluded from classification to focus on full-body kinematics. Differences between groups, with controls, as well as before and after surgery were evaluated for patients reported outcome measures, kinematic features, and spatio-temporal parameters. Three functional groups were identified. One low-functioning cluster with mostly elderly women showing significant functional improvement one year after surgery, and two high-functioning clusters differentiated by pelvis tilt (anteversion vs. retroversion), sagittal knee alignment (varus vs. neutral), and knee flexion during stance phase (flexum vs. extended) that showed limited improvement one year after surgery. Satisfaction rates were similar among clusters and mental scores improved for all clusters. High functioning patients may benefit from TKA, mostly due to pain reduction, but may not see significant improvement of their function, with no clear impact on satisfaction rate. On the contrary, patients with important functional limitation are more likely to improve both pain and functional outcomes. [ABSTRACT FROM AUTHOR]

Given the importance of physical activity (PA) for both physical and mental health, the present study characterizes post-9/11 veterans' leisure-time PA engagement over time. Further, this study examines the relationship between PA and posttraumatic stress symptoms (PTSS), as well as whether this relation differs by gender and time since military discharge. This study was a secondary analysis of a 12-month longitudinal observational investigation of 410 (39.5% female) post-9/11 veterans. Participants completed self-report questionnaires at baseline and 12 months. Over a third of post-9/11 veterans were not engaging in any weekly leisure-time PA at study baseline and PA engagement significantly decreased in the subsequent year. The longitudinal relationship between PA and PTSS depended on both gender and time since military discharge. These results underscore the importance of considering both gender and time since discharge when tailoring interventions to support leisure-time PA as a key health habit in post-9/11 veterans. [ABSTRACT FROM AUTHOR]