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Abstract Metastatic urothelial carcinoma (mUC) is a lethal cancer, with limited therapeutic options. Large-scale studies in early settings provided critical insights into the genomic and transcriptomic characteristics of non-metastatic UC. The genomic landscape of mUC remains however unclear. Using Whole Exome (WES) and mRNA sequencing (RNA-seq) performed on metastatic biopsies from 111 patients, we show that driver genomic alterations from mUC were comparable to primary UC (TCGA data). APOBEC, platin, and HRD mutational signatures are the most prevalent in mUC, identified in 56%, 14%, and 9% of mUC samples, respectively. Molecular subtyping using consensus transcriptomic classification in mUC shows enrichment in neuroendocrine subtype. Paired samples analysis reveals subtype heterogeneity and temporal evolution. We identify potential therapeutic targets in 73% of mUC patients, of which FGFR3 (26%), ERBB2 (7%), TSC1 (7%), and PIK3CA (13%) are the most common. NECTIN4 and TACSTD2 are highly expressed regardless of molecular subtypes, FGFR3 alterations and sites of metastases.

Abstract In clinical practice, the glomerular filtration rate (GFR), a measurement of kidney functioning, is normally calculated using equations, such as the European Kidney Function Consortium (EKFC) equation. Despite being the most general equation, EKFC, just like previously proposed approaches, can still struggle to achieve satisfactory performance, limiting its clinical applicability. As a possible solution, recently machine learning (ML) has been investigated to improve GFR prediction, nonetheless the literature still lacks a general and multi-center study. Using a dataset with 19,629 patients from 13 cohorts, we investigate if ML can improve GFR prediction in comparison to EKFC. More specifically, we compare diverse ML methods, which were allowed to use age, sex, serum creatinine, cystatin C, height, weight and BMI as features, in internal and external cohorts against EKFC. The results show that the most performing ML method, random forest (RF), and EKFC are very competitive where RF and EKFC achieved respectively P10 and P30 values of 0.45 (95% CI 0.44;0.46) and 0.89 (95% CI 0.88;0.90), whereas EKFC yielded 0.44 (95% CI 0.43; 0.44) and 0.89 (95% CI 0.88; 0.90), considering the entire cohort. Small differences were, however, observed in patients younger than 12 years where RF slightly outperformed EKFC.

Abstract Background Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended for the management of acute postoperative pain as part of a multimodal strategy to reduce opioid use, relieve pain, and reduce chronic pain in non-cardiac surgery. However, significant concerns arise in cardiac surgery due to the potential adverse effects of NSAID including increased bleeding and acute kidney injury (AKI). We hypothesized that NSAIDs are effective against pain and safe in the early postoperative period following cardiac surgery, taking contraindications into account. Methods The KETOPAIN trial is a prospective, double blind, 1:1 ratio, versus placebo multicentric trial, randomizing 238 patients scheduled for cardiac surgery. Written consent will be obtained for all participants. The inclusion criterion is patients more than 18 years old undergoing for elective cardiac surgery under cardiopulmonary bypass (CPB). Patients will be allocated to the intervention (ketoprofen) group (n = 119) or the control (placebo) group (n = 119). In the intervention group, in addition to the standard treatment, patients will receive NSAIDs (ketoprofen) at a dose of 100 mg each 12 h 48 h after. The control group, in addition to the standard treatment, will receive a placebo of NSAIDs every 12 h for 48 h after surgery. An intention-to-treat analysis will be performed. The primary endpoint will be the intensity of acute postoperative pain at rest at 24 h from the end of surgery. Pain will be assessed using the numerous rating scale. The secondary endpoints will be postoperative pain on coughing during chest physiotherapy, postoperative pain until day 7, the pain trajectory between day 3 and day 7, cumulative opioid consumption within 48 h after surgery, nausea and vomiting, the occurrence of postoperative pulmonary complications within the first 7 days after surgery, neuropathic pain at 3 months, and quality of life at 3 months. Discussion NSAIDs function as non-selective, reversible inhibitors of the cyclooxygenase enzyme and play a role in a multimodal pain management approach. While there are recommendations supporting the use of NSAIDs in major non-cardiac surgery, recent guidelines do not favor their use in cardiac surgery. However, this is based on low-quality evidence. Major concerns regarding NSAID use in cardiac surgery patients are potential increase in postoperative bleeding or AKI. However, few studies support the possible use of NSAIDs without the risk of bleeding and/or AKI. Also, in a recent French survey, many anesthesiologists reported using NSAIDs in cardiac surgery. To date, no large randomized study has been conducted to evaluate the efficacy of NSAIDs in the management of postoperative pain in cardiac surgery. The expected outcome of this study is an improvement in the management of acute postoperative pain in cardiac surgery with a multimodal strategy including the use of NSAIDs. Trial registration ClinicalTrials.gov NCT06381063. Registered on April 24, 2024.

Abstract Using a new red blood cell (RBC) metabolite extraction protocol, we performed a metabolomic analysis on RBCs in rheumatoid arthritis (RA) patients treated or not with methotrexate (MTX), with the two following objectives: to compare the RBC metabolic profiles of MTX-naïve RA patients and healthy controls (HC), and to investigate whether RBC profiles before and after MTX treatment in RA differed between responders and non-responders. Plasma analysis was performed in parallel. Metabolites were extracted and identified in RBCs and plasma by liquid chromatography-mass spectrometry. We compared the metabolomic fingerprints of 31 DMARD-naïve RA patients and 39 HCs. We also compared the RBC and plasma metabolomes of 25 RA patients who responded or not to MTX therapy before (M0) and after a 3-month treatment period (M3). Significance was determined by Storey’s false discovery rate (FDR) q-values to correct for multiple testing. RA patients and HCs differed in the metabolomic signature of RBCs. The signature mainly contained amino acids (AA). Eleven metabolites, including 4 metabolites belonging to the carbohydrate subclass and 2 amino acids (creatine and valine) showed accumulation in RBCs from RA patients. Conversely, citrulline (fold change = 0.83; q = 0.025), histidine (fold change = 0.86; q = 0.014) and ergothioneine (EGT) (fold change = 0.66; q = 0.024), were lower in RBC of RA patients. Five plasma metabolites, including succinic acid and hydroxyproline, were higher in RA patients, and 7 metabolites, including DHEA sulfate, alanine, threonine and ornithine, were lower. Among RA patients undergoing MTX treatment pre-treatment (M0), EGT values were significantly lower in non-responders. In conclusion, low RBC levels of EGT, a food-derived AA barely detectable in plasma, characterize DMARD naïve RA patients and lack of response to MTX treatment.

The Collisional Orogeny in the Scandinavian Caledonides (COSC) project focuses on processes related to the closure of the Iapetus Ocean, causing the OrdovicianâSilurian continentâcontinent collision between Baltica and Laurentia. The rock succession in the second drill core (COSC-2) from the Jämtland County, central Sweden, provides the base for detailed sedimentological, stratigraphic, geophysical, geochemical, geothermal and structural studies. The basement, comprising 1.66â1.65 Ga Transscandinavian Igneous Belt porphyries intruded by 1.47 Ga and 1.27â1.26 Ga mafic dykes and sills, is heavily weathered towards the top. Here it grades into typical saprock and saprolite (including immature soil reflecting the sub-Cambrian peneplain). The overlying sedimentary sequence starts with basal conglomerates and heterogeneous sediments with shell fragments, indicating an early Cambrian rather than a Neoproterozoic age for the marine transgression in the area. The developing early Cambrian basin was rapidly filled, initially by mostly coarse-grained sediment gravity flows. These strata are covered by sandstone turbidites that show an upward transition into the Alum Shale Formation, representing a tectonically quieter period (mid-Cambrian/Maolingian to Early Ordovician/Tremadocian). The upper part of the Alum Shale Formation is overlain by a late Early Ordovician turbidite succession. Local sources of sediments below the Alum Shale Formation and the extended deposition period may indicate continuous sedimentation in a pull-apart basin preserved in a window beneath the Caledonian thrust sheets.

Abstract Many seafood products marketed as “sustainable” are not. More exacting sustainability standards are needed to respond to a fast-changing world and support United Nations SDGs. Future fisheries must operate on principles that minimise impacts on marine life, adapt to climate change and allow regeneration of depleted biodiversity, while supporting and enhancing the health, wellbeing and resilience of people and communities. We set out 11 actions to achieve these goals.

In Western France, rapeseed (Brassica napus) cultivation faces substantial yield losses due to the root holoparasitic plant Phelipanche ramosa. However, recent observations have shown a reduction in parasitism within previously heavily infested fields. This study investigates two neighboring rapeseed soils with distinct levels of parasitic infestation, considered suppressive and conducive. Using a cocultivation system of Brassica napus and P. ramosa, we comprehensively examined rhizosphere exudates, parasitic plant attachment, and rhizosphere soil microbiota. Our findings revealed that the suppressive soil effectively reduced parasitism by impeding broomrape attachment and development, as well as inducing necrosis of tubercles. This suppressive effect was specific to postattachment stages, leaving germination and haustoriogenesis preattachment stages unaffected. Analysis of microbial structures suggested that the suppression of parasitism is predominantly of fungal rather than bacterial origin. Correlation network analyses identified three groups of amplicon sequence variants (ASVs) associated with suppression. Notably, seven ASVs were inversely correlated with parasitic attachments, and only one ASV, identified as Berkeleyomyces, a necrotrophic fungus responsible for black root rot, was positively correlated with necrosis and was more abundant in the suppressive soil. This study demonstrates the contrasting parasitic plant development on two physicochemically similar soils, highlighting the central role of fungal dynamics in the rhizosphere. These results provide valuable insights into the mechanisms underlying soil-mediated suppression of P. ramosa, offering potential strategies for mitigating the impact of this root holoparasite on rapeseed yields in the region.

Abstract Neutron activation dosimetry is the primary method for the determination of the neutron flux or fluence, and in general, it is sensitive to the thermal and resonance energy ranges (radiative capture reactions– $$(n,\gamma )$$ ( n , γ ) reactions) and the fast energy range (threshold reactions). However, there are very few nuclear reactions which are sensitive specifically to neutrons in the intermediate–epithermal–energy region. This energy region, along with the fast energy range, will become particularly important in the development and deployment of new reactor technologies (Generation IV reactors and Small Modular Reactors–SMRs), which are currently being championed as technologies enabling a meaningful contribution to decarbonization and the fight against climate change, as well as nuclear fusion. The epithermal neutron energy range is also of particular importance for Boron Neutron Capture Therapy (BNCT), a neutron-based cancer therapy, particularly effective for the treatment of head and neck cancer, malignant meningioma, melanoma and hepatocellular carcinoma. This work investigates and demonstrates the applicability of a particular set of $$(n,\gamma )$$ ( n , γ ) reactions in conjunction with boron-based neutron filters to achieve sensitivity in the epithermal energy region, and discusses avenues for future research in this context.

Abstract Background Antimicrobial resistance (AMR) in Enterobacterales constitutes a significant threat to the health of both humans and animals and a socioeconomic problem. Enterobacterales, mainly Escherichia coli, carrying β-lactamases has become one of the main indicators to estimate the burden of AMR in animals within “One Health” approach. Objectives To assess the presence of extended-spectrum cephalosporin-resistant Enterobacterales associated with ruminants (cattle, sheep, goats) habituated in all five provinces of Rwanda and to perform in depth characterization of isolates. Methods We screened 454 rectal swabs from 203 cows, 170 goats, and 81 sheep and selective isolation of extended-spectrum cephalosporin-resistant Enterobacterales was conducted. Isolates were identified as a members of the order Enterobacterales by MALDI-TOF MS and further characterized by susceptibility testing and by whole-genome sequencing. Results Out of the 454 samples, 64 extended-spectrum cephalosporin-resistant Enterobacterales were isolated from 58 animals. Isolates belonged to seven bacterial species and were identified as Escherichia coli (n = 54), Enterobacter bugandensis (n = 4), Enterobacter mori (n = 2), Klebsiella pneumoniae (n = 2), Enterobacter dykesii (n = 1), and Citrobacter freundii (n = 1). All isolates displayed an Extended-spectrum β-lactamases (ESBL) phenotype, with exception of Citrobacter freundii isolate displayed both an ESBL and AmpC phenotype. In addition, all Enterobacter isolates were identified as stably de-repressed AmpC-producers. ESBLs genes, bla CTX−M−15 was predominant. Resistance to tetracycline and tet(A) was most frequently observed among non-β-lactam resistance. Forty-eight isolates displayed multidrug-resistance phenotypes. A shiga toxin-producing E. coli and an enterotoxigenic E. coli isolate were observed. Genome comparisons revealed thirty-five E. coli sequence types (ST) (ST10, ST307 being predominate). Conclusions Considering the high proximity between ruminants and humans in Rwanda, the dissemination of antimicrobial drug resistance highlights the public health threats and requires the joint and multisectoral action of human and veterinary medicine, at human-animal-environment interfaces. Therefore, it is important to establish national and global “One Health” surveillance programs of AMR to tackle the antibiotic-resistant crisis in human and veterinary medicine.

Abstract Group-living organisms commonly exhibit collective escape responses, yet how information flows among group members in these events remains an open question. Here, we study the collective responses of a sheep flock (Ovis aries) to a shepherd dog (border collie) in a driving task between two well-defined target points. We collected high-resolution spatiotemporal data from 14 sheep and the dog, using Ultra-Wide-Band tags attached to each individual. We find that the spatial positions of sheep along the front-back axis of the group’s velocity strongly correlate with their impact on the collective movement. Our analyses reveal that, even though the dog chases the sheep flock from behind, directional information on shorter time scales propagates from the front of the group towards the rear; further, the dog adjusts its movement in response to the flock’s dynamics. We introduce an agent-based model that captures key data features. Specifically, in response to chasing, the sheep change their spatial relative positions less frequently and exhibit a transfer of directional information flow from front to back; this pattern disappears in the absence of chasing. Our study reveals some general insights into how directional information propagates in escaping animal groups.

Abstract Background Risdiplam is a validated treatment for adult SMA patients, but clear guidelines concerning functional assessment at baseline and during the follow-up are still limited, especially in terms of sensible and validated outcome measures able to capture minimal changes in motor performances induced by therapy. The aim of this work is to describe the effect of Risdiplam on a cohort of 6 adult type 2 and type 3 SMA patients, using Motor Function Measure (MFM32) as a standardized scaleto quantify the motor improvements induced by therapy. Results Risdiplam at the dose of 5 mg/daily was administered to a population of 6 (4 F;2 M) type 2 (N = 4) and type 3 (N = 2), adult SMA patients. Two patients were previously treated by Nusinersen, later suspended due to side effects. At baseline, all patients received a neuromuscular evaluation and a MFM32 assessment. After the beginning of treatment, we evaluated MFM32, patient reported outcomes (PROs), and adverse events over 7–27 months of follow-up. The MFM32 showed an increased score ranging from + 2.16% to + 7.29% in 4 patients. The improvement was maintained overtime, with two patients presenting the longest follow-up period of 24 and 27 months respectively. Subdomain D3 was ameliorated in 66.6% of patients. Two patients previously treated with Nusinersen maintained the pre-Risdiplam scores. The HFMSE was also performed and failed to show significant improvements after treatment. All patients reported subjective ameliorations. The commonest PROs were improvements in breath fatigue, voice’s intelligibility, hand strength and dexterity. Adverse effects were mild and decreased over time. Conclusions Risdiplam is a well-tolerated treatment in our cohort of adult type 2 and type 3 SMA patients and resulted in improvement or stabilization in motor functions. MFM32 proved to be sensitive to detect changes induced by therapy. Subjective meaningful improvements were sustained overtime especially in bulbar functions, breath fatigue and distal motor abilities.

Abstract Background Targeted radionuclide therapy with 177Lu-labelled small conjugates is expanding rapidly, and its success is linked to appropriate patient selection. Companion diagnostic conjugates are usually labelled with 68Ga, offering good imaging up to ≈2 h post-injection. However, the optimal tumor-to-background ratio is often reached later. This study examined promising positron-emitting radiometals with half-lives between 3 h and 24 h and β+ intensity (Iβ+) ≥ 15% and compared them to 68Ga. The radiometals included: 43Sc, 44Sc, 45Ti, 55Co, 61Cu, 64Cu, 66Ga, 85mY, 86Y, 90Nb, 132La, 150Tb and 152Tb. 133La (7.2% Iβ+) was also examined because it was recently discussed, in combination with 132La, as a possible diagnostic match for 225Ac. Methods Total electron and photon doses per decay and per positron; possibly interfering γ-ray emissions; typical activities to be injected for same-day imaging; positron range; and available production routes were examined. Results For each annihilation process useful for PET imaging, the total energy released (MeV) is: 45Ti (1.5), 43Sc (1.6), 61Cu and 64Cu (1.8), 68Ga (1.9), 44Sc and 133La (2.9), 55Co (3.2), 85mY (3.3), 132La (4.8), 152Tb (6.5), 150Tb (7.1), 90Nb (8.6), and 86Y (13.6). Significant amounts (≥ 10%) of ≈0.5 MeV photons that may fall into the acceptance window of PET scanners are emitted by 55Co, 66Ga, 85mY, 86Y, 132La, and 152Tb. Compton background from more energetic photons would be expected for 44Sc, 55Co, 66Ga, 86Y, 90Nb, 132La,150Tb, and 152Tb. The mean positron ranges (mm) of 64Cu (0.6), 85mY (1.0), 45Ti (1.5), 133La (1.6), 43Sc and 61Cu (1.7), 55Co (2.1), 44Sc and 86Y (2.5), and 90Nb (2.6) were lower than that of 68Ga (3.6). DOTA chelation is applicable for most of the radiometals, though not ideal for 61Cu/64Cu. Recent data showed that chelation of 45Ti with DOTA is feasible. 90Nb requires different complexing agents (e.g., DFO). Finally, they could be economically produced by proton-induced reactions at medical cyclotrons. Conclusion In particular, 43Sc, 45Ti, and 61Cu have overall excellent β+ decay-characteristics for theranostic applications complementing 177Lu-labelled small conjugates, and they could be sustainably produced. Like Lu, 43Sc, 45Ti and to a lesser extent 61Cu could be labelled with DOTA.

Abstract Cyclones, whether tropical, extratropical, or of Mediterranean origin, play a crucial role in the Earth’s climate system, affecting environments and populations through strong winds, heavy rainfall, and flooding. While much research has focused on tropical and extratropical cyclones, Mediterranean cyclones have received less attention. These cyclones are generally weaker, smaller, and shorter-lived than their tropical or mid-latitude counterparts. However, recent events, such as Mediterranean cyclone Daniel in 2023, which caused severe flooding and thousands of deaths in Libya, underscore the major threat Mediterranean cyclones pose. In this study, we investigate the role of Mediterranean cyclones in triggering floods in Corsica, a region frequently affected by these storms. By analyzing cyclone tracks, streamflow data, and flood-related damage records from Corsica, we reveal a notable rise in river discharge linked to Mediterranean cyclones and show that they contributed to some of the most destructive floods recorded in Corsica between 1979 and 2020.

Anthophora onosmarum is a poorly known bee species described from the Caucasus (Georgia). New fieldwork has revealed that the species is present in Bulgaria and Greece, and is also widespread across Turkey, predominantly on the Anatolian plateau. New behavioural data shows that A. onosmarum is likely narrowly oligolectic on the plant genus Onosma (Boraginaceae), and is capable of buzzing flowers to release pollen. This finding illustrates the growing trend of overlooked bee species with more Caucasian, Anatolian, or even Middle Eastern distributions occurring in under-surveyed mountainous parts of the Southern Balkans.

Abstract Background The ventilatory physiopathology of patients with interstitial lung disease (ILD) remains poorly understood. We aimed to personalize a mechanical simulator to model healthy and ILD profiles ventilation, and to evaluate the effect of spontaneous breathing on respiratory mechanics at rest and during exercise. Methods In a 2-compartment lung simulator (ASL 5000®), we modeled 1 healthy and 3 ILD profiles, at rest and during exercise, based on physiological data from literature and patients. Measurements were: tidal volume, end-expiratory lung volume, driving pressure, transpulmonary driving pressure, dynamic alveolar strain, mechanical power, and time lag of inspiratory flow between compartments 1 and 2. Results Healthy and ILD models were validated: maximum differences between real and simulated tidal volume were 5% (96 ml) and 6% (54 ml) at rest and during exercise respectively, considered clinically negligible. When we simulated lung inhomogeneity (compliance in compartment 1 > compartment 2), tidal volume, end-expiratory lung volume, driving pressure and mechanical power increased in compartment 1 and decreased in compartment 2. Driving transpulmonary pressure and dynamic alveolar strain increased in compartment 2 and decreased in compartment 1. Time lag of inspiratory flow between compartments 1 and 2 was positively correlated with a difference of compliance between compartments (r = 0.98, CI95% (0.9106; 0.9962), p

Abstract Neuroendocrine tumor (NET) is a rare malignant tumor, notably small cell lung cancer (SCLC), a type of lung neuroendocrine tumor, which has a survival rate of less than 7%. Although various biomarkers including CHGA (Chromogranin A), INSM1 (Insulinoma-associated protein 1), and SYP (Synaptophysin) are extensively used for the diagnostic testing of NET, their diverse specificities and sensitivities are acknowledged as limitations. Here, we demonstrate that RepID (Replication initiation determinant protein), a component of CRL4 (Cullin-RING ubiquitin E3 ligase 4), holds promise as a biomarker for identifying NET and SCLC. Analysis of the Cancer Cell Line Encyclopedia (CCLE) via the CellMinerCDB portal reveals a high correlation between RepID transcript levels and mRNA expression of NE signature genes. Additionally, RepID protein is highly expressed in SCLC patient tissues and a subset of SCLC cell lines. Viability analysis following treatment with pevonedistat and SZL-P1-41 in SCLC cell lines and human SCLC-organoid models indicates that RepID expression determines the sensitivity to CRL-targeting anti-cancer drugs. These findings suggest that RepID represents a novel biomarker for NET and SCLC, and insights from RepID research in these cancers could lead to innovative therapeutic strategies.

Abstract The black soldier fly, Hermetia illucens (L. 1758), is an omnivorous saprophagous insect with a high potential for valorizing organic by-products rich in carbohydrates. Among carbohydrates, H. illucens relies on soluble sugars for the growth and storage lipid synthesis. This study aimed to assess the impact of common soluble sugars on the development, survival, and fatty acid composition of H. illucens. Monosaccharides and disaccharides were individually incorporated into a chicken feed diet. Cellulose was used as a control. Larvae fed glucose, fructose, sucrose, and maltose grew faster than control larvae. In contrast, lactose exhibited anti-nutritional effects on larvae, slowing down growth and reducing final individual weight. However, all soluble sugars produced larvae fatter than the control diet. Notably, the tested sugars shaped the fatty acid profile. Maltose and sucrose increased saturated fatty acid content compared to cellulose. Conversely, lactose increased the bioaccumulation of dietary unsaturated fatty acids. This study is the first to demonstrate the effect of soluble sugars on the fatty acid profile of H. illucens larvae. Our findings highlight that the tested carbohydrates have significant effects on black soldier fly fatty acid composition and can thus determine their final applications.

Abstract The Easter mantle plume has produced one of the longest hotspot tracks in the Pacific Ocean. While previous studies have focused on the eastern side extending across the Nazca Plate, we use 40Ar/39Ar isotopic and geochemical data to investigate the less explored western side around the Easter Microplate. We propose a dynamic model in which a deeper (600 km-depth), less buoyant mantle exerts a westward force on the East Pacific Rise (EPR), while a more buoyant plume region drives Easter hotspot volcanism and a localised acceleration in seafloor spreading. Our findings suggest that the Easter hotspot is the more focused surface expression of the most buoyant region of a vast, deep-seated mantle plume extending from the Pacific Large Low Shear Velocity Province (LLSVP). This challenges the traditional view of hotspots as isolated phenomena and suggests they are part of broader LLSVP-related mantle structures. Our results imply a more intricate, large-scale relationship between hotspots, mantle plumes, spreading ridges, and mantle dynamics.

Abstract Vibrio cholerae harbours a primary chromosome derived from the monochromosomal ancestor of the Vibrionales (ChrI) and a secondary chromosome derived from a megaplasmid (ChrII). The coordinated segregation of the replication terminus of both chromosomes (TerI and TerII) determines when and where cell division occurs. ChrI encodes a homologue of Escherichia coli MatP, a protein that binds to a DNA motif (matS) that is overrepresented in replication termini. Here, we use a combination of deep sequencing and fluorescence microscopy techniques to show that V. cholerae MatP structures TerI and TerII into macrodomains, targets them to mid-cell during replication, and delays their segregation, thus supporting that ChrII behaves as a bona fide chromosome. We further show that the extent of the segregation delay mediated by MatP depends on the number and local density of matS sites, and is independent of its assembly into tetramers and any interaction with the divisome, in contrast to what has been previously observed in E. coli.

Abstract Background In unforeseen situations, such as nuclear power plant’s or civilian radiation accidents, there is a need for effective and computationally inexpensive methods to determine the expression level of a selected gene panel, allowing for rough dose estimates in thousands of donors. The new generation in-situ mapper, fast and of low energy consumption, working at the level of single nanopore output, is in demand. We aim to create a sequence identification tool that utilizes natural language processing techniques and ensures a high level of negative predictive value (NPV) compared to the classical approach. Results The training dataset consisted of RNA sequencing data from 6 samples. Multiple natural language processing models were examined, differing in the type of dictionary components (word length, step, context) as well as the encoding length and number of sequences required for algorithm training. The best configuration analyses the entire sequence and uses a word length of 3 base pairs with one-word neighbor on each side. For the considered FDXR gene, the achieved mean balanced accuracy (BACC) was 98.29% and NPV was 99.25%, compared to minimap2’s performance in a cross-validation scenario. The next stage focused on exploring the dictionary components and attempting to optimize it, employing statistical techniques as well as those relying on the explainability of the decisions made. Reducing the dictionary from 1024 to 145 changed BACC to 96.49% and the NPV to 98.15%. Obtained model, validated on an external independent genome sequencing dataset, gave NPV of 99.64% for complete and 95.87% for reduced dictionary. The salmon-estimated read counts differed from the classical approach on average by 3.48% for the complete dictionary and by 5.82% for the reduced one. Conclusions We conclude that for long Oxford nanopore reads, a natural language processing-based approach can reliably replace classical mapping when there is a need for fast, reliable and energy and computationally efficient targeted mapping of a pre-defined subset of transcripts. The developed model can be easily retrained to identify selected transcripts and/or work with various long-read sequencing techniques. Our results of the study clearly demonstrate the potential of applying techniques known from classical text processing to nucleotide sequences.

Erb‐b2 receptor tyrosine kinase 2 (ERBB2)‐activating mutations are therapeutically actionable alterations found in various cancers, including metastatic breast cancer (MBC). We developed multiplex digital PCR assays to detect and quantify ERBB2 mutations in circulating tumor DNA from liquid biopsies. We studied the plasma from 272 patients with hormone‐receptor‐positive, human epidermal growth factor receptor 2‐negative (HR+/HER2−) MBC to detect 17 ERBB2 mutations using a screening assay. The assay was developed on the three‐color Crystal dPCR™ naica® platform with a two‐step strategy for precise mutation identification. We found that nine patients (3.3%) harbored at least one ERBB2 mutation. The mutation rate was higher in patients with lobular histology (5.9%) compared to invasive breast carcinoma of no special type (2.6%). A total of 12 mutations were found with the following frequencies: L755S (25.00%), V777L (25.00%), S310Y (16.67%), L869R (16.67%), S310F (8.33%), and D769H (8.33%). Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma‐based monitoring of ERBB2 mutational status in patients with MBC.

Abstract Internal variability arising from the inherently chaotic nature of the climate system has amplified or obscured human-caused changes, especially at regional scales in the extratropics, where its contribution to climate variability is the largest. It is virtually certain that this will continue in the near-term. We here focus on the Northern Europe region, whose variability is largely controlled by the North Atlantic Oscillation (NAO) and the Atlantic Meridional Overturning Circulation (AMOC) through remote dynamical and thermodynamic processes, and introduce the concept of internal variability storylines (IVS) to explore, understand, and quantify the role of the two combined drivers of internal variability in the modulation of the anthropogenic warming by 2040 in winter. Based on a large ensemble of historical-scenario simulations, we show that the high-impact IVS, characterised by weak AMOC decline and a decadal shift of the NAO toward dominant positive phase, leads faster to warmer-wetter conditions independently of actual and future greenhouse gases emissions. By contrast, amplified AMOC reduction and more recurrent negative NAO can considerably damp both warming and wettening at near-term. In the latter IVS, we provide evidence that winter-severe conditions similar to those in 2010, that had been responsible for widespread socio-economic disruptions, remain almost as likely to occur by 2040. Reframing the uncertain climate outcomes into the physical science space in a conditional form through the prism of IVS makes climate information relevant for accurate risk assessments and adaptation planning.

Abstract 18F-GP1 is a novel highly specific radiotracer that binds to activated platelets and thrombus. We aimed to establish the observer repeatability of coronary, carotid and cerebral 18F-GP1 uptake in patients presenting with acute myocardial infarction or ischaemic stroke. Forty-three patients presenting with acute myocardial infarction or ischaemic stroke underwent hybrid positron emission tomography (PET) and computed tomography (CT) angiography. Qualitative and quantitative assessment of 18F-GP1 uptake was performed on coronary arteries, carotid arteries and brain parenchyma. Qualitative uptake of 18F-GP1 had excellent intraobserver and interobserver agreement, with complete agreement for the presence or absence of visual 18F-GP1 uptake. For quantitative analysis, there were excellent intraclass correlation coefficients for intraobserver repeatability for coronary artery, carotid artery and brain parenchymal SUVmax and TBRmax measurements (all ≥ 0.92). Coronary artery and brain parenchymal analyses showed the strongest agreement in SUVmax values with mean biases of − 0.04 (limits of agreement − 0.21 to 0.20) and 0.02 (limits of agreement − 0.29 to 0.32) respectively. There was good interclass correlation coefficients for interobserver repeatability for coronary artery, carotid artery and brain parenchymal SUVmax and TBRmax measurements (all ≥ 0.89). The strongest interobserver agreement was seen with brain parenchymal SUVmax (mean SUVmax 1.95 ± 0.94) and TBRmax (mean TBRmax 9.55 ± 6.56) with mean biases of − 0.05 (limits of agreement − 0.37 to 0.27) and 0.04 (limits of agreement − 0.59 to 0.52) respectively. Visual qualitative and quantitative 18F-GP1 PET-CT image analyses provide robust and repeatable measurements of activated platelets and thrombi within the coronary arteries, carotid arteries and brain parenchyma.

Abstract White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical ‘atrophy’ identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical ‘atrophy’ showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.

Abstract Occupancy models were originally developed to better understand species distribution while accounting for imperfect detection. Because species distribution is not only shaped by habitat quality but also by the ability of individuals to reach suitable habitats, spatial dynamic occupancy models have been proposed to extend the original framework by defining that site colonisation was a function of the Euclidean distance to occupied sites. However, not all sites in the landscape are equally accessible due to the presence of barriers, that of corridors, etc. To account for connectivity between sites, the Euclidean distance has recently been replaced by a least‐cost path distance, which explicitly accounts for landscape resistance, but assumes that individuals will follow the optimal route. To relax this assumption, we first developed a new spatial occupancy model that incorporates commute‐time distance derived from circuit theory to model accessibility across sites. This distance has the advantage of modelling movement as a random walk and accounting for the fact that colonisation could be achieved from multiple paths. Our approach allows for the explicit estimation of landscape connectivity from detection/non‐detection data and a direct measure of connectivity uncertainty. We implemented the model in the Bayesian framework using the nimble R package, which allows useful R connectivity functions to be called from within the model. Second, we carried out a simulation study to assess the performance of our model by considering four scenarios depicting an increasing level of landscape resistance. Third, to illustrate our new approach, we studied the recolonisation of two carnivores in France. We quantified the degree to which rivers facilitate Eurasian otter (Lutra lutra) colonisation and highways impede Eurasian lynx (Lynx lynx) colonisation. Overall, spatial occupancy models provide a flexible framework to accommodate any distance metric designed to align with species dispersal ecology.

Abstract Focal adhesions (FAs) strengthen their link with the actin cytoskeleton to resist force. Talin-vinculin association could reinforce actin anchoring to FAs by controlling actin polymerization. However, the actin polymerization activity of the talin-vinculin complex is not known because it requires the reconstitution of the mechanical and biochemical activation steps that control the association of talin and vinculin. By combining kinetic and binding assays with single actin filament observations in TIRF microscopy, we show that the association of talin and vinculin mutants, mimicking mechanically stretched talin and activated vinculin, triggers a sequential mechanism in which filaments are nucleated, capped and released to elongate. In agreement with these observations, FRAP experiments in cells co-expressing the same constitutive mutants of talin and vinculin revealed accelerated growth of stress fibers. Our findings suggest a versatile mechanism for the regulation of actin assembly in FAs subjected to various combinations of biochemical and mechanical cues.

Abstract Introduction Current guidelines for pain treatment recommend a personalized, multimodal and interdisciplinary approach as well as the use of a combination of drug and non-drug therapies. Risk factors for chronification should already be reduced in patients with acute pain, e.g., after surgery or trauma. Auricular vagus nerve stimulation (aVNS) could be an effective non-drug therapy in the multimodal treatment of chronic and acute pain. The aim of this systematic review and meta-analysis is to evaluate the clinical efficacy and safety of aVNS in treating chronic and acute pain conditions. Methods A systematic literature search was performed regarding the application of auricular electrical stimulation in chronic and acute pain. Studies were classified according to their level of evidence (Jadad scale), scientific validity and risk of bias (RoB 2 tool) and analyzed regarding indication, method, stimulation parameters, duration of treatment and efficacy and safety. A meta-analysis on (randomized) controlled trials (using different comparators) was performed for chronic and acute pain conditions, respectively, including subgroup analysis for percutaneous (pVNS—needle electrodes) and transcutaneous (tVNS—surface electrodes) aVNS. The visual analog pain scale (VAS) was defined as primary efficacy endpoint. Results A total of n = 1496 patients were treated with aVNS in 23 identified and analyzed studies in chronic pain, 12 studies in acute postoperative pain and 7 studies in experimental acute pain. Of these, seven studies for chronic pain and six studies for acute postoperative pain were included in the meta-analysis. In chronic pain conditions, including back pain, migraine and abdominal pain, a statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control treatment with an effect size Hedges’ g/mean difference of − 1.95 (95% confidence interval [CI]: − 3.94 to 0.04, p = 0.008) could be shown and a more favorable effect in pVNS compared to tVNS (− 5.40 [− 8.94; − 1.85] vs. − 1.00 [− 1.55; − 0.44]; p = 0.015). In acute pain conditions, single studies showed significant improvements with aVNS, e.g., in kidney donor surgery or tonsillectomy but, overall, a non-statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control with − 0.70 [− 2.34; 0.93] (p = 0.15) could be observed in the meta-analysis. In acute pain results vary greatly between studies depending especially on co-medication and timepoints of assessment after surgery. A significant reduction in analgesics or opiate intake was documented in most studies evaluating this effect in chronic and acute pain. In 3 of the 12 randomized controlled trials in patients with chronic pain, a sustainable pain reduction over a period of up to 12 months was shown. Overall, aVNS was very well tolerated. Conclusion This systematic review and meta-analysis indicate that aVNS can be an effective and safe non-drug treatment in patients with specific chronic and acute postoperative pain conditions. Further research is needed to identify the influence of simulation parameters and find optimal and standardized treatment protocols while considering quality-of-life outcome parameters and prolonged follow-up periods. A more standardized approach and harmonization in study designs would improve comparability and robustness of outcomes.

Abstract Chronic histiocytic intervillositis of unknown origin (CHI) is a rare placental disorder associated with adverse pregnancy outcomes, frequent recurrence, and a lack of effective preventive strategies. Recent insights indicate a potential link between CHI-associated inflammatory lesions and the inflammasome pathway, suggesting innovative therapeutic avenues. Here we show a potential role of the inflammasome pathway in CHI through comprehensive transcriptomic analysis of grade 2 or 3 histopathologic CHI samples, paired with placental controls. Additionally, we present case studies of three individuals with recurrent CHI, who have undergone treatment with anakinra and colchicine throughout pregnancy, resulting in improved perinatal outcomes. Notably, all cases are characterized by the birth of healthy, full-term infants, with reduced or absent intervillositis recurrence. Placental assessment unveils heightened activation of the NLRP3-PYCARD inflammasome pathway and IL-1β processing in CHI samples, with downregulation observed in treated pregnancy samples, devoid of intervillositis. Collectively, these findings suggest a potential therapeutic role for targeting the inflammasome pathway in preventing recurrent CHI in pregnant individuals.

Abstract Intrinsically disordered regions (IDRs) are highly enriched in the nucleolar proteome but their physiological role in ribosome assembly remains poorly understood. Our study reveals the functional plasticity of the extremely abundant lysine-rich IDRs of small nucleolar ribonucleoprotein particles (snoRNPs) from protists to mammalian cells. We show in Saccharomyces cerevisiae that the electrostatic properties of this lysine-rich IDR, the KKE/D domain, promote snoRNP accumulation in the vicinity of nascent rRNAs, facilitating their modification. Under stress conditions reducing the rate of ribosome assembly, they are essential for nucleolar compaction and sequestration of key early-acting ribosome biogenesis factors, including RNA polymerase I, owing to their self-interaction capacity in a latent, non-rRNA-associated state. We propose that such functional plasticity of these lysine-rich IDRs may represent an ancestral eukaryotic regulatory mechanism, explaining how nucleolar morphology is continuously adapted to rRNA production levels.

Abstract The morbidity of aneurysmal subarachnoid hemorrhage (aSAH) remains high, particularly because of secondary cerebral lesions that significantly aggravate the primary lesions. The main type of secondary lesions is delayed cerebral ischemia (DCI), in which platelets (PLT) appear to play a key role. Mean platelet volume (MPV) is an indirect marker of platelet activation. We aimed to determine the individual trajectories of MPV over time in patients with and without DCI during the course of aSAH. This is a single-center, retrospective, longitudinal analysis of individual trajectories of MPV over time, in a cohort of aSAH patients included in the Prospective, Observational Registry of Patient with Subarachnoid Hemorrhage in Neurocritical Care Unit (ProReSHA). A mixed-effects linear regression model was used to compare the trajectories of MPV and MPV/PLT ratio between patients who developed a DCI and those who did not. A total of 3634 MPV values were collected in 587 patients. The analysis of MPV as a function of DCI occurrence showed a significant difference in the trajectory over time between patients with DCI and those without, with an estimate of 0.02 (95%CI 0.01, 0.04, p = 0.009). The analysis of the MPV/PLT ratio as a function of DCI occurrence and other covariates showed a significant difference in the trajectory over time only for patients with a modified Fisher score less than 3, with an estimate of -0.59 (95%CI: -0.94, -0.23, p = 0.001). The individual trajectories of MPV over time differ between patients with DCI and those without. However, MPV values vary greatly over time and between patients. Thus it does not appear as a reliable biomarker for stratifying patients based on their specific risk of developing DCI. ClinicalTrials.gov identifier: (NCT02890004), registered in August 2016.

Abstract The purpose of this study is to objectively assess by polysomnography total sleep time and sleep macrostructure in glaucomatous versus non-glaucomatous individuals after adjusting for possible confounding factors affecting the quality of sleep. This is an observational, prospective, single-center, case-controlled study using a sleep research database (MARS e-Cohort) collecting clinical data, comorbidities, medications, and sleep studies of glaucomatous and non-glaucomatous individuals. The diagnosis of glaucoma was confirmed with a full comprehensive ophthalmological examination including a visual field test. Total sleep time and the main sleep parameters (time spent in stages 1, 2, 3 and 4, microarousals, apnea–hypopnea index, and indices of hypoxic burden) were compared in glaucomatous and non-glaucomatous individuals after adjusting for age, anthropometric data, and comorbidities. The study included 33 glaucomatous and 66 non-glaucomatous individuals. The median total sleep time was 325 min [273; 398] for the control group and 311 min [244; 349] for the glaucoma group. After adjusting for the potential confounding factors, there was no significant difference in total sleep time (p = 0.3) and other sleep parameters between the control group and the glaucoma group. The sleep macrostructure was comparable in the glaucomatous and non-glaucomatous individuals after careful adjustment for confounders.

Abstract Chronic obstructive pulmonary disease (COPD) is an etiologically complex disease characterized by acute exacerbations and stable phases. We aimed to identify biological functions modulated in specific COPD conditions, using whole blood samples collected in the AERIS clinical study (NCT01360398). Considered conditions were exacerbation onset, severity of airway obstruction, and presence of respiratory pathogens in sputum samples. With an integrative multi-network gene community detection (MNGCD) approach, we analyzed expression profiles to identify communities of correlated genes. The approach combined different layers of gene interactions for each explored condition/subset of samples: gene expression similarity, protein-protein interactions, transcription factors, and microRNAs validated regulons. Heme metabolism, interferon-alpha, and interferon-gamma pathways were modulated in patients at both exacerbation and stable-state visits, but with the involvement of distinct sets of genes. An important gene community was enriched with G2M checkpoint, E2F targets, and mitotic spindle pathways during exacerbation. Targets of TAL1 regulator and hsa−let−7b − 5p microRNA were modulated with increasing severity of airway obstruction. Bacterial infections with Moraxella catarrhalis and, particularly, Haemophilus influenzae triggered a specific cellular and inflammatory response in acute exacerbations, indicating an active reaction of the host to infections. In conclusion, COPD is a complex multifactorial disease that requires in-depth investigations of its causes and features during its evolution and whole blood transcriptome profiling can contribute to capturing some relevant regulatory mechanisms associated with this disease. In this work, we explored multi-network modeling that integrated diverse layers of regulatory gene networks and enhanced our comprehension of the biological functions implicated in the COPD pathogenesis.

Abstract Debris-flow activity in the Alps is anticipated to undergo pronounced changes in response to a warming climate. Yet, a fundamental challenge in comprehensively assessing changes in process activity is the systematic lack of long-term observational debris-flow records. Here, we reconstruct the longest, continuous time series (1626-2020) of debris flows at Multetta, a supply-limited torrential system in the Eastern Swiss Alps. Relying on growth-ring records of trees that were damaged by debris flows, we do not detect significant changes in the frequency or magnitude over time. This seeming absence of a direct climatic influence on debris-flow initiation aligns with the regular distribution of repose time patterns, indicating a dependence of local process activity on sediment discharge and recharge. This stark difference in process behavior between our supply-limited site and transport-limited catchments has implications for assessing torrential hazard and risk mitigation in a context of global warming.

Abstract Introduction This study evaluates the gait analysis obtained by Inetial Measurement Units (IMU) before and after surgical management of Spastic Equino Varus Foot (SEVF) in hemiplegic post-stroke patients and to compare it with the functional results obtained in a monocentric prospective cohort. Methods Patients with post-stroke SEVF, who underwent surgery in a single hospital between November 2019 and December 2021 were included. The follow-up duration was 6 months and included a functional analysis using Goal Attainment Scaling (GAS) and a Gait analysis using an innovative Multidimensional Gait Evaluation using IMU: the semiogram. Results 20 patients had a gait analysis preoperatively and at 6 months postoperatively. 90% (18/20) patients had a functional improvement (GAS T score ≥ 50) and 50% (10/20) had an improvement in walking technique as evidenced by the cessation of the use of a walking aid (WA). In patients with functional improvement and modification of WA the change in the semiogram area was + 9.5%, sd = 27.5%, and it was + 15.4%, sd = 28%. In the group with functional improvement without change of WA. For the 3 experiences (two patients) with unfavorable results, the area under the curve changed by + 2.3%, -10.2% and − 9.5%. The measurement of the semiogram area weighted by average speed demonstrated very good reproducibility (ICC(1, 3) = 0.80). Discussion IMUs appear to be a promising solution for the assessment of post-stroke hemiplegic patients who have undergone SEVF surgery. They can provide a quantified, objective, reliable in individual longitudinal follow up automated gait analysis solution for routine clinical use. Combined with a functional scale such as the GAS, they can provide a global analysis of the effect of surgery.

Abstract The decline in regeneration efficiency after birth in mammals is a significant roadblock for regenerative medicine in tissue repair. We previously developed a computational agent based-model (ABM) that recapitulates mechanical interactions between cells and the extracellular-matrix (ECM), to investigate key drivers of tissue repair in adults. Time calibration alongside a parameter sensitivity analysis of the model suggested that an early and transient decrease in ECM cross-linking guides tissue repair toward regeneration. Consistent with the computational model, transient inhibition or stimulation of fiber cross-linking for the first six days after subcutaneous adipose tissue (AT) resection in adult mice led to regenerative or scar healing, respectively. Therefore, this work positions the computational model as a predictive tool for tissue regeneration that with further development will behave as a digital twin of our in vivo model. In addition, it opens new therapeutic approaches targeting ECM cross-linking to induce tissue regeneration in adult mammals.

Abstract The exponential increase in sequencing data calls for conceptual and computational advances to extract useful biological insights. One such advance, minimizers, allows for reducing the quantity of data handled while maintaining some of its key properties. We provide a basic introduction to minimizers, cover recent methodological developments, and review the diverse applications of minimizers to analyze genomic data, including de novo genome assembly, metagenomics, read alignment, read correction, and pangenomes. We also touch on alternative data sketching techniques including universal hitting sets, syncmers, or strobemers. Minimizers and their alternatives have rapidly become indispensable tools for handling vast amounts of data.

Abstract Background Colorectal cancer is a public health issue and was the third leading cause of cancer-related death worldwide in 2022. Early diagnosis can improve prognosis, making screening a central part of colorectal cancer management. Blood-based screening, diagnosis and follow-up of colorectal cancer patients are possible with the study of cell-free circulating tumor DNA. This study aimed to identify novel DNA methylation biomarkers of colorectal cancer that can be used for the follow-up of patients with colorectal cancer. Methods A DNA methylation profile was established in the Gene Expression Omnibus (GEO) database (n = 507) using bioinformatics analysis and subsequently confirmed using The Cancer Genome Atlas (TCGA) database (n = 348). The in silico profile was then validated on local tissue and cell-free DNA samples using methylation-specific digital PCR in colorectal cancer patients (n = 35) and healthy donors (n = 35). Results The DNA methylation of COL25A1 and METAP1D was predicted to be a colorectal cancer biomarker by bioinformatics analysis (ROC AUC = 1, 95% CI [0.999–1]). The two biomarkers were confirmed with tissue samples, and the combination of COL25A1 and METAP1D yielded 49% sensitivity and 100% specificity for cell-free DNA. Conclusion Bioinformatics analysis of public databases revealed COL25A1 and METAP1D DNA methylation as clinically applicable liquid biopsies DNA methylation biomarkers. The specificity implies an excellent positive predictive value for follow-up, and the high sensitivity and relative noninvasiveness of a blood-based test make these biomarkers compatible with colorectal cancer screening. However, the clinical impact of these biomarkers in colorectal cancer screening and follow-up needs to be established in further prospective studies.

Abstract The multi-phase oxidation of S(IV) plays a crucial role in the atmosphere, leading to the formation of haze and severe pollution episodes. We here contribute to its understanding on a molecular level by reporting experimentally determined pK a values of the various S(IV) tautomers and reaction barriers for SO2 formation pathways. Complementary state-of-the-art molecular-dynamics simulations reveal a depletion of bisulfite at low pH at the liquid-vapor interface, resulting in a different tautomer ratio at the interface compared to the bulk. On a molecular-scale level, we explain this with the formation of a stable contact ion pair between sulfonate and hydronium ions, and with the higher energetic barrier for the dehydration of sulfonic acid at the liquid-vapor interface. Our findings highlight the contrasting physicochemical behavior of interfacial versus bulk environments, where the pH dependence of the tautomer ratio reported here has a significant impact on both SO2 uptake kinetics and reactions involving NO x and H2O2 at aqueous aerosol interfaces.

Abstract The effect of past environmental changes on the demography and genetic diversity of natural populations remains a contentious issue and has rarely been investigated across multiple, phylogenetically distant species. Here, we perform comparative population genomic analyses and demographic inferences for seven widely distributed and ecologically contrasting European forest tree species based on concerted sampling of 164 populations across their natural ranges. For all seven species, the effective population size, N e , increased or remained stable over many glacial cycles and up to 15 million years in the most extreme cases. Surprisingly, the drastic environmental changes associated with the Pleistocene glacial cycles have had little impact on the level of genetic diversity of dominant forest tree species, despite major shifts in their geographic ranges. Based on their trajectories of N e over time, the seven tree species can be divided into three major groups, highlighting the importance of life history and range size in determining synchronous variation in genetic diversity over time. Altogether, our results indicate that forest trees have been able to retain their evolutionary potential over very long periods of time despite strong environmental changes.

Abstract Background Attrition continues to be a major hurdle for addiction treatment. Through the prism of the attachment theory, this phenomenon can be understood as a manifestation of the patient’s insecure attachment style, needing a highly-responsive care delivery. We developed an electronic health mobile application, co-designed with patients, aimed at helping healthcare teams respond to their patients’ needs, and fostering adherence to care. This acceptability study evaluated patients everyday use of the application for eight weeks, assessing their satisfaction with the system, and its integration within professionals’ current practice in our center. Methods This single-center, prospective study was conducted between January 2022 and December 2022. 24 adult patients with any type of addiction were included. They were granted access to the application for eight weeks, and were invited to complete the System Usability Scale questionnaire regarding their satisfaction with application’s usability at the end of the study. The application uses active self-reports, which are later discussed with the healthcare team, and foster both the working alliance and the decision-making process. Results 17 patients out of 24 reached the primary endpoint. On average, over the eight-weeks period, patients logged in the application 38.2 times, and sent 5.9 messages to the healthcare team. Interestingly, 64.3% of the user logins were recorded outside of our center’s working hours (either from 5 p.m. to 9 a.m., or during week-ends and bank holidays), and 70.8% of the patients logged into the application at least one time between 10 p.m. and 8 a.m. 18 patients completed the System Usability Scale questionnaire, which averaged a score of 81.8 out of 100. Healthcare professionals logged in the application’s messaging system 4.5 times a day on average. Conclusions This preliminary study shows promising results, as patients engaged well with various components of the application. It was moreover possible for healthcare workers in our center to integrate this tool in their daily activities. More work is needed to better understand the various patients’ needs regarding the application, further strengthen their adherence to the intervention, and understand professionals’ motivations to use the application. Trial registration ClinicalTrials.gov, Identifier: NCT04659954. Registered 09 December 2020, https://clinicaltrials.gov/study/NCT04659954 .

Abstract Background BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. Methods Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. Results DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. Conclusions The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. Trial registration: NCT02674152 and NCT02689505.

Abstract Background This narrative review was written by an expert panel to the members of the jury to help in the development of clinical practice guidelines on oxygen therapy. Results According to the expert panel, acute hypoxemic respiratory failure was defined as PaO2

Abstract Radiotherapy represents a major curative treatment for prostate cancer (PCa), but some patients will develop radioresistance (RR) and relapse. The underlying mechanisms remain poorly understood, and miRNAs might be key players in the acquisition and maintenance of RR. Through their encapsulation in small extracellular vesicles (EVs), they can also be relevant biomarkers of radiation response. Using next-generation sequencing, we found that miR-200c-3p was downregulated in PCa RR cells and in their small EVs due to a gain of methylation on its promoter during RR acquisition. We next showed that its exogenous overexpression restores the radiosensitivity of RR cells by delaying DNA repair through the targeting of HP1α. Interestingly, we also observed downregulation of miR-200c-3p expression by DNA methylation in radiation-resistant lung and breast cancer cell lines. In summary, our study demonstrates that the downregulation of miR-200c-3p expression in PCa cells and in their small EVs could help distinguish radioresistant from sensitive tumor cells. This miRNA targets HP1α to delay DNA repair and promote cell death.

Abstract Background Implementation of recommended gestational weight gain (GWG) care by antenatal care providers is poor. It is unclear whether practice implementation and barriers differ between antenatal care provider profession or experience. This study aimed to assesses the provision of and barriers to guideline care for GWG and examine associations with professional discipline and years of experience. Methods A cross sectional survey was conducted with antenatal care providers working in three public maternity services in a regional city in Australia. Data were collected on the provision of and barriers (informed by the Theoretical Domains Framework) to recommended GWG care. Data were summarised using descriptive statistics. Associations between health profession characteristics (professional discipline and years providing antenatal care) and GWG care practices and barrier outcomes were assessed using multivariate logistic regression. Results 117 antenatal care providers completed the survey (75% participation rate). One quarter (25%) reported that they routinely provided recommended GWG assessment at the first antenatal visit, and 9% at subsequent visits. Only 7% routinely provided recommended advice on GWG, healthy eating and physical activity. Professional discipline or years of experience were not associated with higher odds of GWG practices. Skills, belief about capabilities, belief about consequences and environmental context and resources were barriers to providing care. Medical professionals had higher odds of agreeing that they have been adequately trained to address GWG (OR = 9.14, 95%CI:3.10–26.90) and feel competent in having sensitive conversations with pregnant women about GWG (OR = 8.60, 95%CI:2.29–32.28) than midwives. Midwives had higher odds of agreeing that there are services they can refer pregnant women to for further support (OR = 2.80, 95%CI:1.13–6.91). Conclusions The provision of antenatal care for GWG was low, inconsistently provided and did not differ by professional discipline or years of experience. Antenatal care providers report numerous barriers including skills, belief about capabilities, belief about consequences, and environmental context and resources. Barriers to GWG care provision differed by professional discipline, but not years of providing care. The findings demonstrate that the type and prioritisation of practice-change implementation strategies may need to be tailored to address the differential barriers faced by professional groups.

Abstract Branching enzymes (BEs) confer to α-glucans, the primary energy-storage reservoir in nature, a variety of features, like slow digestion. The full catalytic cycle of BEs can be divided in six steps, namely two covalent catalytic steps involving glycosylation and transglycosylation, and four noncatalytic steps involving substrate binding and transfers (SBTs). Despite the ever-growing wealth of biochemical and structural information on BEs, clear mechanistic insights into SBTs from an industrial-performance perspective are still missing. Here, we report a Rhodothermus profundi BE (RpBE) endowed with twice as much enzymatic activity as the Rhodothermus obamensis BE currently used in industry. Furthermore, we focus on the SBTs for RpBE by means of large-scale computations supported by experiment. Engineering of the crucial positions responsible for the initial substrate-binding step improves enzymatic activity significantly, while offering a possibility to customize product types. In addition, we show that the high-efficiency substrate-transfer steps preceding glycosylation and transglycosylation are the main reason for the remarkable enzymatic activity of RpBE, suggestive of engineering directions for the BE family.

Abstract Background Lyme borreliosis is the most frequent zoonotic disease in the northern hemisphere and is transmitted by ticks of the genus Ixodes. Although many people are bitten by ticks in private yards, our understanding of the factors associated with their presence in these areas remains limited. To address this gap, we used a citizen science approach to identify the local and landscape features associated with tick presence in yards. Methods This study was conducted near Nancy, a city in northeastern France, from 2020 to 2022. Citizen scientists collected ticks in their yard on a single event (n = 185) and measured 13 yard features. Additionally, we computed 11 features related to the landscape composition and spatial configuration surrounding these yards. Using generalized linear mixed models, we determined the yard and landscape features associated with the presence of ticks and nymphal Ixodes ricinus (hereafter nymphs), the life stage, and species that mostly bite humans. Results Despite a low density, ticks were found in 32% of the yards, including yards in urbanized areas. At the transect level, the likelihood of finding a nymph was nearly three times higher in transects shaded by vegetation compared to those in open areas, with no relationship between nymph occurrence and transect location or grass height. At the yard level, the occurrence of ticks and nymphs was related to both yard and landscape characteristics. Nymph and tick occurrence were more than twice as high in yards with signs of deer and a wood/brush pile compared to those without these characteristics, and increased with the connectivity of vegetation areas and the percentage of forest areas in the landscape. Conclusions Our study reveals that private yards across an urbanization gradient are locations of tick exposure with tick presence linked to both yard and landscape factors. These findings emphasize the importance of public awareness regarding tick exposure in yards and provide crucial insights for future public health prevention campaigns.

Abstract Background The ageing population, coupled with the desire to age-in-place, highlight the need for programs that target health promotion as a means of maintaining functional ability, autonomy, and independence among community-dwelling older adults. This paper describes the development of the VIeSA intervention, which aimed to model a healthy ageing trajectory, including the identification of the necessary tools and methods, that would allow people older people, in partnership with health and social care professionals, to define personal health-related goals and the actions to achieve them. A key element of the intervention development was the creation of a support tool intended to assist this process. Methods The UK Medical Research Council (MRC) guidance on developing and evaluating complex interventions was applied in the development of the intervention and of the support tool. A participatory approach was selected, with stakeholders engaged on different occasions to allow the refinement of the intervention and of the support tool. Following the steps and suggested actions in the MRC development phase, the development process was conducted by identifying (1) the evidence base and (2) the theoretical framework and (3) by modelling the process and outcomes of the intervention. Results Following a literature review on effective interventions for functional ability, draft 1 of the support tool was designed. Focus groups with stakeholders provided feedback on this draft allowing for its refinement in terms of content, language use, and structure (draft 2). A review of the approaches for health promotion delivery led to further additions to the tool (draft 3) and informed the content of the training of health and social care professionals. After their training, professionals provided feedback on the acceptability, appropriateness, and feasibility of different elements of the intervention. Results suggested that no further major refinement to the intervention or support tool was necessary. Conclusions The design and development of the VIeSA intervention using the MRC guidance allowed for a clarity of direction, an optimised content in terms of usefulness and accessibility for all concerned stakeholders, and greater opportunities for its implementation and uptake.

Abstract Background Current AT(N) stratification for Alzheimer’s disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. Methods This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. Results As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. Conclusions The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and aggressive liver cancer with limited therapeutic options. Precise classification and immunotherapy are perspectives to improve the treatments. We reported the role of septin 9 in apico‐basal polarity and epithelial‐to‐mesenchymal transition (EMT). Here, we aim to elucidate its role in iCCA. We analyzed single‐cell transcriptomes from human iCCA tumor cells based on phenotype and cell state. Knockdown of the septin 9 gene (SEPT9) was done using small interfering RNA (siRNA); interferon‐γ (IFN‐γ) stimulation was performed using different CCA cells; gene expressions were analyzed by reverse transcription and real‐time PCR analysis (RT‐qPCR); and immunofluorescence, immunoblotting, and flow cytometry were performed to assess the expression of proteins. The differential distributions of SEPT9 and vimentin (VIM) gene expressions allowed us to define specific cellular trajectories of malignant cells and thus identified distinct clusters of iCCA cells. One cluster was enriched in VIM and extracellular‐matrix (ECM) remodeling molecules, and another had high expression of SEPT9 and genes from the ‘don't eat me’ signal involved in immune escape. This antagonism between SEPT9 and VIM was confirmed by in vitro experiments. Notably, SEPT9 and ‘don't eat me’ gene expressions were inversely correlated to those of vimentin and the EMT markers. SEPT9 expression was upregulated by IFN‐γ and SEPT9 knockdown decreased expression of ‘don't eat me’ signal genes and increased expression of mesenchymal markers. Cancer Cell Line Encyclopedia (CCLE) transcriptome database analyses confirmed that iCCA cells enriched in septin 9 exhibit epithelial‐like features. This study revealed septin 9 as a cytoskeleton element of iCCA epithelial‐like cells and a regulator of the immune system response. It also brings new insights into the enigmatic relationship between EMT and immune response. Notably, we decoded a potential mechanism that could sensitize patients to immunotherapies.