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Abstract This paper explores the response to Holocene ash inundation in different sub‐environments of two fluvio‐lacustrine systems, Las Piedritas and Totoral, focussing on the processes of volcaniclastic remobilisation. Sediment cores and outcrops were used to recognise three deposit types, noting how some differ from lahars, through sedimentological and stratigraphic analysis: (1) thick, laterally discontinuous, pumice‐dominated deposits occur overlying alluvial plain and lower terrace surfaces across both watersheds; (2) chaotic, extremely poorly sorted and matrix‐supported beds composed of both epiclastic and pyroclastic material occur as two conspicuous deposits at Las Piedritas outcrops, in a low‐gradient confined channel setting; and (3) layers with an exclusively pyroclastic composition and no flow sedimentary structures or fragment roundness were found draping each of the two chaotic intervals and intercalating with the background sediment in Las Piedritas prodelta. Thick pumice packages capping the floodplains resulted from the overflow of streams carrying a floating pumice load. Due to its positive buoyancy, the pumice is transported as a slowly moving overlying mantle without mixing with the streamflow. The disorganised pattern and poor sorting of the matrix‐rich polymictic beds are consistent with laminar, gravity‐driven, high‐concentration flows. They constitute secondary lahars, originating upstream from large run‐off processes that reworked a pyroclastic substrate. The lack of reworking features in the vitric‐rich units identified in the lake core retrieved from Las Piedritas prodelta, as well as the continuous and widespread occurrences of those interbedded in upstream outcrops, indicate an airfall origin. No reworked tephra unit is recognised in the prodelta sediment record, although various deposits from the hydrologic remobilisation of airfall tephra are found along the subaerial portion of both watersheds. Apparently, large amounts of flotation‐remobilised tephra were retained on the delta plain, while another considerable fraction would have been carried away from the creek mouth under the influence of dominant regional winds.

Abstract This study evaluates the safety and potential benefits of PBM on pancreatic beta cells and islets. PBM was applied to insulin-secreting cell lines (MIN6) and rat pancreatic islets using a 670 nm light source, continuous output, with a power density of 2.8 mW/cm², from 5 s to several 24 h. Measure of cell viability, insulin secretion, mitochondrial function, ATP content, and cellular respiration were assessed. Additionally, a diabetic rat model is used for islet transplantation (pre-conditioning with PBM or not) experiments. Short and long-term PBM exposure did not affect beta cell islets viability, insulin secretion nor ATP content. While short-term PBM (2 h) increases superoxide ion content, this was not observed for long exposure (24 h). Mitochondrial respirations were slightly decreased after PBM. In the islet transplantation model, both pre-illuminated and non-illuminated islets improved metabolic control in diabetic rats with a safety profile regarding the post-transplantation period. In summary, for the first time, long-term PBM exhibited safety in terms of cell viability, insulin secretion, energetic profiles in vitro, and post-transplantation period in vivo. Further investigation is warranted to explore PBM’s protective effects under conditions of stress, aiding in the development of innovative approaches for cellular therapy.

Summary: Background: We apply endoscopic ultrasound-guided fine needle aspiration biopsy to cytopathologically diagnose and sample nucleic acids from primary tumours regardless of the disease stage. Methods: 397 patients with proven pancreatic adenocarcinoma were included and followed up in a multicentre prospective study. DNA and mRNA were extracted from materials of primary tumours obtained by endoscopic ultrasound-guided fine needle aspiration biopsy and analysed using targeted deep sequencing and RNAseq respectively. Findings: The variant allele frequency of the KRAS mutation was used to evaluate the tumour cellularity, ranging from 15 to 20% in all cells, regardless of the tumour stage. The molecular profile of metastatic primary tumours significantly differed from other types of tumours, more frequently having TP53 mutations (p = 0.0002), less frequently having RNF43 mutations, and possessing more basal-like mRNA component (p = 0.001). Molecular markers associated with improved overall survival were: mutations in homologous recombination deficiency genes in patients who received first-line platinum-based chemotherapy (p = 0.025) and wild-type TP53 gene in patients with locally advanced tumours who received radio-chemotherapy (p = 0.01). The GemPred transcriptomic profile was associated with a significantly better overall survival in patients with locally advanced or metastatic pancreatic cancer who received a gemcitabine-based first-line treatment (p = 0.019). Interpretation: The combination of genomic and transcriptomic analyses of primary pancreatic tumours enables us to distinguish metastatic tumours from other tumour types. Our molecular strategy may assist in predicting overall survival outcomes for platinum or gemcitabine-based chemotherapies, as well as radio-chemotherapy. Funding: Institut National Du Cancer (BCB INCa_7294), CHU of Toulouse, Inserm and Ligue Nationale Contre le Cancer (CIT program).

We developed a hands-on activity using the game Jenga to demonstrate the links between health behaviors, chronic and infectious diseases, and community well-being and resilience. For the activity, K-12 students worked together in small teams (4-8 students) and were given two Jenga towers ("tower A" and "tower B"), each representing a community of individuals. The goal was to keep both towers standing. Teams were presented with strips of paper labeled with either a "health behavior" (e.g., nutrition, body weight maintenance, physical activity) or a "disease" (e.g., heart disease, diabetes, COVID-19) and instructions on whether to add or remove blocks from each tower. When presented with a health behavior, students added blocks to "tower A" for positive health behaviors (e.g., not smoking) and removed blocks from "tower B" for negative health behaviors (e.g., smoking). When a disease was presented students removed blocks from both towers, but fewer blocks were removed from "tower A" compared with "tower B," demonstrating lower disease rates or severity in that community. As the activity progressed, "tower A" retained more blocks than "tower B". For the finale, students observed that the greater strength and stability of "tower A" allowed it to withstand a simulated natural disaster such as an earthquake better than "tower B". This activity was delivered to 15 science classes and 225 students ranging from 6th to 12th grade. Students were able to describe the connections between positive health behaviors and lower rates of disease and how, taken together, these impact community health, well-being, and resilience.

Abstract Cancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal. Here, we characterize a new OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and uncoupling effect. MS-L6 is effective on both intact and sub-mitochondrial particles, indicating that its efficacy does not depend on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines. MS-L6 either dose-dependently inhibits cell proliferation or induces cell death in a variety of cancer cell lines, including B-cell and T-cell lymphomas as well as pediatric sarcoma. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI-1) partially restores the viability of B-lymphoma cells treated with MS-L6, demonstrating that the inhibition of NADH oxidation is functionally linked to its cytotoxic effect. Furthermore, MS-L6 administration induces robust inhibition of lymphoma tumor growth in two murine xenograft models without toxicity. Thus, our data present MS-L6 as an inhibitor of OXPHOS, with a dual mechanism of action on the respiratory chain and with potent antitumor properties in preclinical models, positioning it as the pioneering member of a promising drug class to be evaluated for cancer therapy. MS-L6 exerts dual mitochondrial effects: ETC-I inhibition and uncoupling of OXPHOS. In cancer cells, MS-L6 inhibited ETC-I at least 5 times more than in isolated rat hepatocytes. These mitochondrial effects lead to energy collapse in cancer cells, resulting in proliferation arrest and cell death. In contrast, hepatocytes which completely and rapidly inactivated this molecule, restored their energy status and survived exposure to MS-L6 without apparent toxicity.

Foot and mouth disease (FMD) is a highly contagious viral disease affecting cloven-hoofed animals. This disease is one of the most important in animal health due to its significant socio-economic impact, especially in case of an outbreak. One important challenge associated with this disease is the ability of the FMD virus (FMDV) to persist in its hosts through still unresolved underlying mechanisms. The absence of relevant in vitro models is one factor preventing advancement in our understanding of FMDV persistence. While a primary bovine cell model has been established using cells from FMDV primary and persistence site in cattle, it appeared interesting to develop a similar model based on ovine anatomical sites of interest to compare host-pathogen interactions. Thus, epithelial cells derived from the palatine tonsils and the dorsal soft palate were isolated and cultured. Their epithelial nature was confirmed using immunofluorescence. Following monolayer infection with FMDV O/FRA/1/2001 Clone 2.2, the FMDV-sensitivity of these cells was evaluated. Dorsal soft palate (DSP) cells were also expanded in multilayers at the air-liquid interface to mimic a stratified epithelium sensitive to FMDV infection. Our investigation revealed the presence of infectious virus, as well as viral antigens and viral RNA, up to 35 days after infection of the cell multilayers. Further experiment with DSP cells from different individuals needs to be reproduced to confirm the robustness of the new model of persistence in multilayer DSP. The establishment of such primary cells creates new opportunities for FMDV research and analysis in sheep cells.

The bone–patellar tendon–bone (BPTB) autograft or allograft is a well-established option for primary or revision anterior cruciate ligament (ACL) reconstruction. However, although the length and width of the graft are relatively consistent, its thickness is unpredictable and can impact the biomechanical properties of the ACL graft. This technical note describes a technique for arthroscopic ACL reconstruction called the “BPTB-plus” technique, which consists of a BPTB graft augmented by the gracilis tendon.

Posterior cruciate ligament (PCL) ruptures are uncommonly seen in knee ligament injuries. Cconservative treatment is often suitable for isolated tears with mild-to-moderate posterior knee laxity (grades I or II). However, surgical intervention is indicated for symptomatic grade III or multiligament knee injuries. PCL reconstruction has experienced continuous development due to the progress made in arthroscopic techniques and instruments. Abnormal positioning and tensioning of the femoral button result in multiple complications such as residual laxity, loss of quadriceps muscle strength, and joint stiffness. In this Technical Note, we describe direct arthroscopic visualization of the femoral button deployment in PCL reconstruction technique, and we discuss its importance to prevent complications related to button malposition.

Background: Arthrogenic muscle inhibition (AMI) is a complex neurological phenomenon that is actually very common. AMI can appear following a knee injury or knee surgery. If it is not addressed, the patient's function can be negatively affected. There is currently no specific tool for the diagnosis and treatment of AMI. Indications: Following surgery or injury to the knee, AMI causes defective activation of the quadriceps, sometimes combined with a knee extension deficit. A clinical classification of AMI has been proposed recently to help with making the diagnosis and to guide treatment. In this article, we describe how biofeedback and surface electromyography (EMG) can be used in the early diagnosis and treatment of knee AMI. Technique Description: Biofeedback is based on transformation of physiological variables into a visual or auditory signal. This allows the patient to learn how to control physical and bodily functions, which were previously considered as involuntary processes. This technique requires the use of a specific device that transforms the measured physiological signals—neuromuscular activation in this instance—into visual signals. This tool incorporates surface EMG, with electrodes connected to a measuring unit. This unit is connected to a screen that shows the neuromuscular activation in real time. Thus, EMG biofeedback can be used to help clinicians make a diagnosis and to specifically treat the AMI. Results: We have used biofeedback in patients who have a knee injury or who have undergone knee surgery. Both the therapist and patient were able to objectively see the presence of AMI using the biofeedback device. For treatment, the therapist works with a patient by providing clear instructions and increasingly more challenging goals. We show examples of how patients were able to eliminate their AMI by using biofeedback. Discussion/Conclusion: EMG biofeedback is a promising tool for the diagnosis and treatment of AMI after an anterior cruciate ligament (ACL) tear and ACL reconstruction surgery. The next steps are to define thresholds and a rehabilitation protocol that will be used in a clinical trial. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Calcineurin inhibitors (CNIs) are critical in preventing rejection posttransplantation but pose an increased risk of post-transplant diabetes (PTD). Recent studies show that late conversion from CNIs to belatacept, a costimulation blocker, improves HbA1c in kidney transplant recipients with PTD or de novo diabetes. This study investigates whether the observed effects on PTD stem solely from CNI withdrawal or if belatacept influences PTD independently. The study assessed the impact of tacrolimus and belatacept on insulin secretion in MIN6 cells (a beta cell line) and rat islets. Tacrolimus and belatacept were administered to the cells and islets, followed by assessments of cell viability and insulin secretion. Tacrolimus impaired insulin secretion without affecting cell viability, while belatacept showed no detrimental effects on either parameter. These findings support clinical observations of improved HbA1c upon switching from tacrolimus to belatacept. Belatacept holds promise in islet or pancreas transplantation, particularly in patients with unstable diabetes. Successful cases of islet transplantation treated with belatacept without severe hypoglycemia highlight its potential in managing PTD. Further research is needed to fully understand the metabolic changes accompanying the transition from CNIs to belatacept. Preserving insulin secretion emerges as a promising avenue for investigation in this context.

High-content imaging approaches, in combination with the use of perturbing agents such as small molecules or CRISPR-driven gene editing, have widely contributed to the identification of new therapeutic compounds. Thanks to recent advances in image-analysis methods, the use of high-content screens is increasingly gaining popularity and thus accelerating the discovery of new therapeutics. However, due to the lack of fully biocompatible fluorescent markers, large-scale high-content screens are mostly performed on fixed cells, which complicates the monitoring of changes in cell physiology over time.Here we present a novel fluorescent nontoxic dye that displays intensity and staining pattern changes in response to different physiological states. With multiparametric image analysis, these unique properties allow not only for the detection of distinct phenotypic fingerprints, but also for the quantification of more traditional disease-relevant phenotypes such as apoptosis, autophagy, ER stress and more. Since the dye only gets fluorescent when incorporated into cellular membranes, it is typically used without washing steps, therefore making it ideal to include in automation workflows. In this work, we present ​​relevant data on its biocompatibility and its potential to quantitatively assess subtle cellular phenotypes. Applications such as live kinetic imaging, and live image-based morphological profiling are also discussed. The rich information this fluorescent probe provides facilitates unbiased quantitative phenotypic analysis at larger scale, and ultimately paves the way for more discoveries of new therapeutic agents.

Background Patellar tendinopathy (PT) is a common condition characterised by persistent patellar tendon pain and dysfunction, particularly in athletes. Neovascularisation is frequently observed in the PT and is associated with increased pain. Ultrasound-guided electrocoagulation of neovascularisation has emerged as a minimally invasive alternative treatment for recalcitrant PT.Hypothesis/purpose The purpose of this study was to evaluate the clinical outcomes of ultrasound-guided electrocoagulation of neovascularisation in athletes with persistent PT.Study design Case series; level of evidence, IV.Methods A retrospective analysis of prospectively collected data was performed on 25 athletes who underwent ultrasound-guided electrocoagulation of neovascularisation for recalcitrant PT. Clinical outcomes including complications, reinterventions and patient-reported outcome measures were recorded. Comparisons between variables were assessed using χ2 test or Fisher’s exact test for categorical variables and Student’s t-test or Wilcoxon test for quantitative variables.Results 25 patients were included in the final analysis. 96% returned to their preoperative activity level at a mean of 3.8 months. At a mean follow-up of 5 years 4% did not receive significant benefit from electrocoagulation therapy. Significant improvements were observed in outcome measures, including the Victorian Institute of Sport Assessment Questionnaire for Patients with Patellar Tendinopathy, Kujala score, modified Blazina score and Visual Analogue Scale for pain.Conclusion Ultrasound-guided electrocoagulation of neovascularisation for persistent PT in elite athletes resulted in a low complication rate, a high rate and rapid return to sport and a significant improvement in outcome measures.

Abstract Background Combating malnutrition and cachexia is a core challenge in oncology. To limit muscle mass loss, the use of proteins in cancer is encouraged by experts in the field, but it is still debated due to their antagonist effects. Indeed, a high protein intake could preserve lean body mass but may promote tumour growth, whereas a low‐protein diet could reduce tumour size but without addressing cachexia. Here we used a realistic rodent model of cancer and chemotherapy to evaluate the influence of different protein intakes on cachexia, tumour response to chemotherapy and immune system response. The goal is to gain a closer understanding of the effect of protein intake in cancer patients undergoing chemotherapy. Methods Female Fischer 344 rats were divided into six groups: five groups (n = 14 per group) with cancer (Ward colon tumour) and chemotherapy were fed with isocaloric diets with 8%, 12%, 16%, 24% or 32% of caloric intake from protein and one healthy control group (n = 8) fed a 16% protein diet, considered as a standard diet. Chemotherapy included two cycles, 1 week apart, each consisting of an injection of CPT‐11 (50 mg/kg) followed by 5‐fluorouracil (50 mg/kg) the day after. Food intake, body weight, and tumour size were measured daily. On day 9, the rats were euthanized and organs were weighed. Body composition was determined and protein content and protein synthesis (SUnSET method) were measured in the muscle, liver, intestine, and tumour. Immune function was explored by flow cytometry. Results Cancer and chemotherapy led to a decrease in body weight characterized by a decrease of both fat mass (−56 ± 3%, P

Interfacing long-lived qubits with propagating photons is a fundamental challenge in quantum technology. Cavity and circuit quantum electrodynamics (cQED) architectures rely on an off-resonant cavity, which blocks the qubit emission and enables a quantum non-demolition (QND) dispersive readout. However, no such buffer mode is necessary for controlling a large class of three-level systems that combine a metastable qubit transition with a bright cycling transition, using the electron shelving effect. Here we demonstrate shelving of a circuit atom, fluxonium, placed inside a microwave waveguide. With no cavity modes in the setup, the qubit coherence time exceeds 50 μs, and the cycling transition's radiative lifetime is under 100 ns. By detecting a homodyne fluorescence signal from the cycling transition, we implement a QND readout of the qubit and account for readout errors using a minimal optical pumping model. Our result establishes a resource-efficient (cavityless) alternative to cQED for controlling superconducting qubits.