Swiss School of Archaeology in Greece
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Response to Correspondence on: 'First experience from 200 cases with a new breast tissue expander for multi-stage pre-pectoral breast reconstruction after mastectomy'
No full textSelective striatal pathological changes in a novel human HTT exon 1 knock-in mouse model of Huntington's disease
No full textHuntington's disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by progressive motor deficits, cognitive decline, and psychiatric disturbances caused by expanded CAG repeats in the huntingtin gene (HTT). Despite the development of various animal models, achieving a comprehensive model that closely replicates the biological mechanisms in order to test therapeutic modalities remains a challenge. Here, we describe a novel human HTT exon 1 knock-in (HEKI-150Q) mouse model that incorporates a 3.465-kb human HTT sequence with 150 polyglutamine and successfully mimics key aspects of HD. Behavioral analysis revealed motor dysfunction, hyperactivity, and cognitive deficits similar to those observed in a human HD clinical manifestation. HEKI-150Q mice exhibited age-dependent motor impairment progression with significant phenotypic changes observed starting at six months of age. Histopathological analysis demonstrated the accumulation of mutant huntingtin aggregates, selective striatal neuronal dysfunction, and increased gliosis, further confirming the model's validity for HD research. HEKI-150Q mice thus provide a valuable tool for studying the pathogenic mechanisms of HD and testing potential therapeutic strategies, particularly those targeting human HTT exon 1.
Copyright © 2025. Published by Elsevier Inc
Engineering intercellular communication using M13 phagemid and CRISPR-based gene regulation for multicellular computing in Escherichia coli.
No full textEngineering multicellular consortia, where information processing is distributed across specialized cell types, offers a promising strategy for implementing sophisticated biocomputing systems. However, a major challenge remains in establishing orthogonal intercellular communication, or "wires," within synthetic bacterial consortia. In this study, we address this bottleneck by integrating phagemid-mediated intercellular communication with CRISPR-based gene regulation for multicellular computing in synthetic E. coli consortia. We achieve intercellular communication with high sensitivity by regulating the transfer of single guide RNAs (sgRNAs) encoded on M13 phagemids from sender to receiver cells. Once inside the receiver cells, the transferred sgRNAs mediate gene regulation via CRISPR interference. Leveraging this approach, we successfully constructed one-, two-, and four-input logic gates. Our work expands the toolkit for intercellular communication and paves the way for complex information processing in synthetic microbial consortia, with diverse potential applications, including biocomputing, biosensing, and biomanufacturing
The impact of habitat fragmentation on bacterial interactions and community formation
No full textBacteria live in natural communities of remarkable diversity and spatial complexity, which shape their ecological functions. These functions emerge from community assembly and development processes and cannot be predicted from individual members alone. Understanding the principles of microbial community formation is essential to restoring, optimizing, or controlling their functions for environmental, plant, animal, and human health. A key question in community assembly is the role of space: at the microbial scale, most natural habitats are spatially fragmented and disconnected, which can modulate community propagation and functioning by creating physical barriers to dispersal and altering interspecific interactions. This question remains underexplored because most studies use homogeneously mixed liquid cultures. The goal of this thesis was to investigate the underlying processes by which habitat fragmentation influences community assembly. First, I generated a flexible but controllable experimental system to culture bacterial consortia of varying diversity in fragmented conditions, consisting of emulsions of picolitre-volume culture droplets generated by microfluidics with embedded low cell numbers. The droplets are shielded, and bacteria cannot escape their boundaries, being forced to grow within their confinement and substrate conditions. In my first research chapter, using time-lapse microscopy imaging of pairs of fluorescently-labeled bacteria with defined global interaction types, I showed how fragmentation in droplets favors low-frequency overturning of alternative interaction outcomes, because of founder cell phenotypic variation. This suggests that one important role of habitat fragmentation for microbial diversity is to help slow-growing species escape competition and maintain. In my second chapter, I encapsulated and cultured a more diverse community of 21 defined species. By combining a variety of experimental tools and mathematical models, I could show that habitat fragmentation also acts through the initial founder cell distribution. The fewer the founder cells per droplet habitat, the less they interacted, whereas in case of more founder cells and species per droplet, fast competitors tended to dominate the community. As a result, more species can co-exist and grow at intermediate fragmentation levels. Finally, by encapsulating human-stool-derived communities to different degrees of starting fragmentation, I showed how high fragmentation can alleviate antibiotic inhibition, allowing more taxa to survive than in non-fragmented conditions. My results thus demonstrate the importance of habitat fragmentation for community assembly and functioning, by profoundly altering the overall strength of unfolding interspecific interactions
The Council of Europe Convention on Artificial Intelligence and Human Rights: a primarily procedural step towards safeguarding health rights in the digital age
No full textIn September 2024, the Council of Europe adopted a framework convention on artificial intelligence, human rights, democracy, and the rule of law. As the first global human rights treaty on AI with a broad material and territorial scope, the Convention represents a significant step toward addressing the transnational effects of AI, including its potential impact on health rights. This article argues that the Convention, in particular, introduces new procedural guarantees for patients under the jurisdiction of contracting states, thereby enhancing the effectiveness of their existing health rights. However, the drafters did not fully capitalize on the opportunity to adapt these rights to the digital context or adopt a transversal approach to human rights, including economic, social, and cultural rights. As a result, the Convention offers limited substantive added value in specifying health rights in the digital age
Heterozygous females from a rat model for creatine transporter deficiency reveal altered behavioral response to stressors, normal body weight and slight metabolic changes.
No full textCreatine (Cr) is an organic acid essential for recycling ATP, important in tissues with high energy demand such as muscle or brain. Cr is synthesized in a 2-step pathway by the enzymes AGAT and GAMT, and transported by SLC6A8 (also called CrT). Cerebral Cr deficiency syndromes (CCDS), due to AGAT, GAMT or CrT deficiencies, are metabolic diseases characterized by brain Cr deficiency, causing a range of clinical features such as severe neurodevelopmental delays and intellectual disability, behavioral disturbances, motor dysfunction and epilepsy. Among CCDS, the X-linked CrT deficiency (CTD) is the most prevalent with no efficient treatment so far. Increasing number of human and animal studies contributes to the understanding of CTD pathology, its diagnosis and treatment, and the roles of Cr and CrT. However, most of them are focused in males and little is known about female carriers and how CrT deficiency affect them. In order to increase knowledge in female sex and roughly explore the relationship with SLC6A8 gene dosage, we present the first characterization of females' Slc6a8 Y389C rat model of CTD using both heterozygous and homozygous females. Brain Cr deficiency was found in all homozygous females, while heterozygous ones showed broad variability in brain Cr levels. Elevated and slightly elevated urinary Cr/Crn ratio were present in homozygous and heterozygous females, respectively. Reduced body weight, muscular mass and locomotor activity were hallmarks of homozygous, but not heterozygous, females. However, in contrast to Slc6a8 Y389C KI males, spontaneous alternation and grooming behaviors were not affected in any type of Slc6a8 Y389C mutant female rats. Interestingly, both Slc6a8 Y389C mutant female rats exhibited behavioral abnormalities such as increased prevalence of altered behavioral response to handling, being more frequent in homozygous female rats. Moreover, heterozygous females presented increased anxiety-like behavior to novelty in Open Field Novel Object test and altered behavioral response with increased locomotor activity in response to light as stressor in the Light Dark Box test. These results are coherent with the limited data from CTD human female carriers, validating the Slc6a8 Y389C rat females as a promising tool to better understand CTD in female sex. They also provide new insights about CTD pathology, revealing sex and zygotic phenotypic differences, highlighting the importance of including females in the study of CTD
Pragmatic and contextualized methods selection for safety assessment of infant systemic exposure through human milk: the Milk4baby decision tree approach - a contribution from the concePTION project
No full textMore than 50% of women take at least one medication during lactation. However, 54% of drugs in the LactMed database lack lactation safety data, and only 2% have robust evidence. This highlights a significant gap in guidance for designing pharmacokinetic and safety studies characterizing infant safety following medication exposure during lactation, despite FDA guidelines recommending clinical lactation studies. Additional guidance is needed to select the most suitable study design for these studies. To address this, we identified key medication-related characteristics essential for designing lactation studies that assess infant safety following systemic exposure during lactation. This allowed us to develop a decision tree, named Milk4baby, to guide researchers in selecting the most appropriate methodological approach for each medication. Milk4baby was designed by reviewing the literature and iterative discussions with an interdisciplinary panel of experts in clinical pharmacology, lactation, and pharmacometrics on factors influencing the selection of the methodological approach and design of a lactation study. The decision tree first considers the prevalence of medication utilization in women of childbearing age. Next, the medication's safety profile in infants aged 0-2 years must be assessed using available safety data from infants, adults, and/or animals. Finally, the expected infant systemic exposure level is evaluated based on medication's oral bioavailability, transfer into human milk, risk of accumulation, and utilization patterns. After completing these steps, the decision tree recommends the most suitable methodological approach including case reports/case studies, population pharmacokinetic (popPK) modeling, physiologically based pharmacokinetic (PBPK) modeling and simulations, or pharmacoepidemiologic studies. Verification of the decision tree on 50 randomly selected medications from the LactMed and Le CRAT databases revealed that PBPK and case reports were the most appropriate approaches in 29 cases, primarily due to low prevalence of medication utilization. Designing popPK, PBPK, or pharmacoepidemiologic studies can be time-consuming and resource-intensive, while poorly designed case reports/case studies may yield limited or misleading information. Therefore, Milk4baby aims to help researchers enhance the efficiency and accuracy of determining infant safety following systemic exposure during lactation by choosing the most suitable strategy for lactation studies, ultimately supporting better-informed decisions for lactating women and their healthcare providers.
Copyright © 2025 Monfort, Macente, Van Neste, Huang, Nauwelaerts, Abza, Winterfeld, Smits, Allegaert, Annaert, Guidi and Panchaud
Value of projectional imaging relative to cross-sectional imaging to assess catheter tip position in the superior vena cava: evaluation of reader variability.
No full textThe cavo-atrial junction (CAJ) is the most appropriate central venous catheters CVC tip location to reduce complications. Among chest X-ray (CXR) landmarks for tips assessment, only the pericardial reflection lies in the same plane as the vascular structures. We aimed to evaluate the observer variability to determine tip positioning on CXR, using CT as a gold standard.
We retrospectively analyzed 107 CT scans of patients with port catheters (January-December 2021). The tip to CAJ distance (DCAJ) was measured on both projectional (PJ) and cross-sectional (CS) CT images by 2 × 2 observers (within and between evaluations). Observational statistics included paired t-tests, repeatability coefficients (RC), and intraclass correlation coefficients (ICC), with data visualized using Bland-Altman plots.
All ICC were >0.9, indicating excellent reliability. The mean difference between observers comparing CS and PJ was 0.13 ± 0.80 cm (P = .10) with outer 95% confidence limits of 1.92 cm and -2.17 cm and an RC of 1.79 cm.
CXR provides a reliable method for CVC tip localization, though assessment variability is ±2 cm.
CXR assessment of CVC tips shows both intra- and inter-individual variability, due to challenges in identifying the CAJ and catheter tip . While considering the 3 cm anatomical zone around the CAJ acceptable, operators should be aware of the 2 cm variability resulting from CXR assessment. To account for this variability and avoid the risk of positioning the tip beyond 3 cm from the CAJ, operators should reduce the CXR-based acceptable zone to 1 cm around the CAJ, impacting approximately 30% of procedures
Depletion-dependent activity-based protein profiling using SWATH/DIA-MS detects serine hydrolase lipid remodeling in lung adenocarcinoma progression.
No full textSystematic inference of enzyme activity in human tumors is key to understanding cancer progression and resistance to therapy. However, standard protein or transcript abundances are blind to the activity status of the measured enzymes, regulated, for example, by active-site amino acid mutations or post-translational protein modifications. Current methods for activity-based proteome profiling (ABPP), which combine mass spectrometry (MS) with chemical probes, quantify the fraction of enzymes that are catalytically active. Here, we describe depletion-dependent ABPP (dd-ABPP) combined with automated SWATH/DIA-MS, which simultaneously determines three molecular layers of studied enzymes: i) catalytically active enzyme fractions, ii) enzyme and background protein abundances, and iii) context-dependent enzyme-protein interactions. We demonstrate the utility of the method in advanced lung adenocarcinoma (LUAD) by monitoring nearly 4000 protein groups and 200 serine hydrolases (SHs) in tumor and adjacent tissue sections routinely collected for patient histopathology. The activity profiles of 23 SHs and the abundance of 59 proteins associated with these enzymes retrospectively classified aggressive LUAD. The molecular signature revealed accelerated lipoprotein depalmitoylation via palmitoyl(protein)hydrolase activities, further confirmed by excess palmitate and its metabolites. The approach is universal and applicable to other enzyme families with available chemical probes, providing clinicians with a biochemical rationale for tumor sample classification