The fate of a suppressed X-linked meiotic driver: experimental evolution in Drosophila simulans.

Sex-ratio (SR) meiotic drivers are X-linked selfish genetic elements that promote their own transmission by preventing the production of Y-bearing sperm, which usually lowers male fertility. The spread of SR drivers in populations is expected to trigger the evolution of unlinked drive suppressors, a theoretically predicted co-evolution that has been observed in nature. Once completely suppressed, the drivers are expected either to decline if they still affect the fitness of their carriers, or to evolve randomly and possibly get fixed if the suppressors eliminate their deleterious effects. To explore this issue, we used the Paris sex-ratio system of Drosophila simulans in which drive results from the joint effect of two elements on the X chromosome: a segmental duplication and a deficient allele of the HP1D2 gene. We set up six experimental populations starting with 2/3 of X chromosomes carrying both elements (XSR) in a fully suppressing background. We let them evolve independently during almost a hundred generations under strong sexual competition, a condition known to cause the rapid disappearance of unsuppressed Paris XSR in previous experimental populations. In our study, the fate of XSR chromosomes varied among populations, from extinction to their maintenance at a frequency close to the starting one. While the reasons for these variable outcomes are still to be explored, our results show that complete suppression can prevent the demise of an otherwise deleterious XSR chromosome, turning a genetic conflict into cooperation between unlinked loci. Observations in natural populations suggest a contrasting fate of the two elements: disappearance of the duplication and maintenance of deficient HP1D2 alleles.

Perceptions of general practitioners towards the services provided by advanced practice nurses: a cross-sectional survey in France.

BACKGROUND: New healthcare professions are emerging due to scarce medical resources. The appearance of a new healthcare profession, advanced practice nurses (APNs), has raised questions about how general practitioners interrelate with them as primary care providers. The objective of this study was to explore the perceptions general practitioners have towards the services rendered by APNs to patients, to general practice and the role they play in the healthcare system. METHODS: A survey-based, cross-sectional study was conducted throughout the Grand Est region of France which covers 57,333km2 and has a population of approximately 5,562,651. The survey was compiled using pre-existing questionnaires and was carried out from July to September 2022 via email. Variables collected were rate of acceptability and socio-demographic characteristics. RESULTS: In total, 251 responses were included. The mean age of general practitioners was 41.7 years, most were women (58.2%) and worked in rural areas of the region (53.8%). Over 80% of respondents practiced in group structures (defined as either multi-professional health centers (n = 61) or in group practices (n = 143)). Most respondents (94.0%) were familiar with the APN profession and did not consider that APNs improved access to care (55.8%, percent of responders with score ≤ 3/10). Moreover, most did not believe that APNs were useful as a primary care provider for patients (61.8%). However, being a member of a territorialized healthcare community, known as Communautés Professionnelles Territoriales de Santé (CPTS), was associated with a positive appraisal of APNs' services (OR = 2.116, 95%CI: 1.223 to 3.712; p = 0.007). CONCLUSIONS: Encouraging shared and networked practice within a healthcare community may promote a positive perception of new actors. Further studies need to be conducted to show whether the integration of APNs into healthcare networks improves quality of care.

Long-term outcomes of ilio-sacral screws in minimally invasive bipolar fusionless technique for neuromuscular scoliosis: a retrospective study in 167 patients.

INTRODUCTION: Pelvic fixation in patients with neuromuscular scoliosis is difficult, due to their fragile general condition and poor bone quality. Many techniques have been described, associated with high rates of mechanical complications. The objective of this work was to evaluate the mechanical complications and long-term radiological results of ilio-sacral screw pelvic fixation. MATERIALS AND METHODS: 167 consecutive patients with neuromuscular scoliosis who underwent minimally invasive bipolar fixation with ilio-sacral screw pelvic fixation were retrospectively reviewed. The instrumentation consisted in a bilateral sliding rods construct extended from T1 to the sacrum, anchored proximally by double-hook claws and distally by ilio-sacral screws through a minimally invasive approach. Mechanical complications and radiographic measurements (angle of the major coronal curve, pelvic obliquity, lumbar lordosis) were evaluated preoperatively, postoperatively, and at the last follow-up. RESULTS: Mean operative age was 12 ± 3 years, and follow-up 6.4 years (3.0-10.4 years). Pelvic obliquity decreased from 20° preoperatively to 5° (77% correction) at last follow-up, Angle of the major coronal curve from 75° to 36° (52% correction), and lumbar lordosis from 28° to 38°. 16 mechanical complications in nine patients occurred: screw prominence (n = 1), connector failure (n = 4), screw malposition (n = 11). Unplanned surgery was required in seven cases, two were managed during rod lengthening, seven did not require treatment. CONCLUSION: In this series of neuromuscular patients operated by ilio-sacral screws as pelvic fixation, the results were stable with a mean follow-up of more than 6 years and the complication rate was reduced comparatively to the literature.

[Towards freedom to claim the right to die]. / Vers une liberté à revendiquer le droit à mourir.

current evolution of society makes it possible to debate the issue of the end of life for people suffering from pathologies in which the vital prognosis is not involved; this concerns psychiatric situations in particular. This debate, which bears the seeds of a real desire to die as a personal choice, is likely to profoundly modify the doctor-patient relationship in the particular field of psychiatry.

X-chromosome meiotic drive in Drosophila simulans: a QTL approach reveals the complex polygenic determinism of Paris drive suppression.

Meiotic drivers are selfish genetic elements that promote their own transmission into the gametes, which results in intragenomic conflicts. In the Paris sex-ratio system of Drosophila simulans, drivers located on the X chromosome prevent the segregation of the heterochromatic Y chromosome during meiosis II, and hence the production of Y-bearing sperm. The resulting sex-ratio bias strongly impacts population dynamics and evolution. Natural selection, which tends to restore an equal sex ratio, favors the emergence of resistant Y chromosomes and autosomal suppressors. This is the case in the Paris sex-ratio system where the drivers became cryptic in most of the natural populations of D. simulans. Here, we used a quantitative trait locus (QTL) mapping approach based on the analysis of 152 highly recombinant inbred lines (RILs) to investigate the genetic determinism of autosomal suppression. The RILs were derived from an advanced intercross between two parental lines, one showing complete autosomal suppression while the other one was sensitive to drive. The confrontation of RIL autosomes with a reference XSR chromosome allowed us to identify two QTLs on chromosome 2 and three on chromosome 3, with strong epistatic interactions. Our findings highlight the multiplicity of actors involved in this intragenomic battle over the sex ratio.

Rapid evolution of a Y-chromosome heterochromatin protein underlies sex chromosome meiotic drive.

Sex chromosome meiotic drive, the non-Mendelian transmission of sex chromosomes, is the expression of an intragenomic conflict that can have extreme evolutionary consequences. However, the molecular bases of such conflicts remain poorly understood. Here, we show that a young and rapidly evolving X-linked heterochromatin protein 1 (HP1) gene, HP1D2, plays a key role in the classical Paris sex-ratio (SR) meiotic drive occurring in Drosophila simulans Driver HP1D2 alleles prevent the segregation of the Y chromatids during meiosis II, causing female-biased sex ratio in progeny. HP1D2 accumulates on the heterochromatic Y chromosome in male germ cells, strongly suggesting that it controls the segregation of sister chromatids through heterochromatin modification. We show that Paris SR drive is a consequence of dysfunctional HP1D2 alleles that fail to prepare the Y chromosome for meiosis, thus providing evidence that the rapid evolution of genes controlling the heterochromatin structure can be a significant source of intragenomic conflicts.

Polyploidy and interspecific hybridization: partners for adaptation, speciation and evolution in plants.

Background: Polyploidy or whole-genome duplication is now recognized as being present in almost all lineages of higher plants, with multiple rounds of polyploidy occurring in most extant species. The ancient evolutionary events have been identified through genome sequence analysis, while recent hybridization events are found in about half of the world's crops and wild species. Building from this new paradigm for understanding plant evolution, the papers in this Special Issue address questions about polyploidy in ecology, adaptation, reproduction and speciation of wild and cultivated plants from diverse ecosystems. Other papers, including this review, consider genomic aspects of polyploidy. Approaches: Discovery of the evolutionary consequences of new, evolutionarily recent and ancient polyploidy requires a range of approaches. Large-scale studies of both single species and whole ecosystems, with hundreds to tens of thousands of individuals, sometimes involving 'garden' or transplant experiments, are important for studying adaptation. Molecular studies of genomes are needed to measure diversity in genotypes, showing ancestors, the nature and number of polyploidy and backcross events that have occurred, and allowing analysis of gene expression and transposable element activation. Speciation events and the impact of reticulate evolution require comprehensive phylogenetic analyses and can be assisted by resynthesis of hybrids. In this Special Issue, we include studies ranging in scope from experimental and genomic, through ecological to more theoretical. Conclusions: The success of polyploidy, displacing the diploid ancestors of almost all plants, is well illustrated by the huge angiosperm diversity that is assumed to originate from recurrent polyploidization events. Strikingly, polyploidization often occurred prior to or simultaneously with major evolutionary transitions and adaptive radiation of species, supporting the concept that polyploidy plays a predominant role in bursts of adaptive speciation. Polyploidy results in immediate genetic redundancy and represents, with the emergence of new gene functions, an important source of novelty. Along with recombination, gene mutation, transposon activity and chromosomal rearrangement, polyploidy and whole-genome duplication act as drivers of evolution and divergence in plant behaviour and gene function, enabling diversification, speciation and hence plant evolution.

Local dynamics of a fast-evolving sex-ratio system in Drosophila simulans.

By distorting Mendelian transmission to their own advantage, X-linked meiotic drive elements can rapidly spread in natural populations, generating a sex-ratio bias. One expected consequence is the triggering of a co-evolutionary arms race between the sex chromosome that carries the distorter and suppressors counteracting its effect. Such an arms race has been theoretically and experimentally established and can have many evolutionary consequences. However, its dynamics in contemporary populations is still poorly documented. Here, we investigate the fate of the young X-linked Paris driver in Drosophila simulans from sub-Saharan Africa to the Middle East. We provide the first example of the early dynamics of distorters and suppressors: we find consistent evidence that the driving chromosomes have been rising in the Middle East during the last decade. In addition, identical haplotypes are at high frequencies around the two co-evolving drive loci in remote populations, implying that the driving X chromosomes share a recent common ancestor and suggesting that East Africa could be the cradle of the Paris driver. The segmental duplication associated with drive presents an unusual structure in West Africa, which could reflect a secondary state of the driver. Together with our previous demonstration of driver decline in the Indian Ocean where suppression is complete, these data provide a unique picture of the complex dynamics of a co-evolutionary arms race currently taking place in natural populations of D. simulans.

Ultra-low power high temperature and radiation hard complementary metal-oxide-semiconductor (CMOS) silicon-on-insulator (SOI) voltage reference.

This paper presents an ultra-low power CMOS voltage reference circuit which is robust under biomedical extreme conditions, such as high temperature and high total ionized dose (TID) radiation. To achieve such performances, the voltage reference is designed in a suitable 130 nm Silicon-on-Insulator (SOI) industrial technology and is optimized to work in the subthreshold regime of the transistors. The design simulations have been performed over the temperature range of -40-200 °C and for different process corners. Robustness to radiation was simulated using custom model parameters including TID effects, such as mobilities and threshold voltages degradation. The proposed circuit has been tested up to high total radiation dose, i.e., 1 Mrad (Si) performed at three different temperatures (room temperature, 100 °C and 200 °C). The maximum drift of the reference voltage V(REF) depends on the considered temperature and on radiation dose; however, it remains lower than 10% of the mean value of 1.5 V. The typical power dissipation at 2.5 V supply voltage is about 20 µW at room temperature and only 75 µW at a high temperature of 200 °C. To understand the effects caused by the combination of high total ionizing dose and temperature on such voltage reference, the threshold voltages of the used SOI MOSFETs were extracted under different conditions. The evolution of V(REF) and power consumption with temperature and radiation dose can then be explained in terms of the different balance between fixed oxide charge and interface states build-up. The total occupied area including pad-ring is less than 0.09 mm2.

Characterization of Polymeric Composites for Hydrogen Tank.

Carbon neutrality has led to a surge in the popularity of hydrogen tanks in recent years. However, designing high-performance tanks necessitates the precise determination of input material properties. Unfortunately, conventional characterization methods often underestimate these material properties. To address this limitation, the current research introduces alternative designs of ring tensile specimens, which enable accurate and reliable characterization of filament-wound structures. The advantages and disadvantages of these alternative designs are thoroughly discussed, considering both numerical simulations and experimental investigations. Moreover, the proposed ring tensile methods are applied to characterize thermoplastic composites for hydrogen storage tanks. The results indicate that the mechanical strengths and stiffness of carbon fiber-reinforced thermoplastic Elium® 591 composites closely match those of epoxy-based composites. This newfound accuracy in measurement is expected to contribute significantly to the development of recyclable hydrogen tanks.

Inhaled dry powder cisplatin increases antitumour response to anti-PD1 in a murine lung cancer model.

Despite advances in targeted therapies and immunotherapy in lung cancer, chemotherapy remains the backbone of treatment in most patients at different stages of the disease. Inhaled chemotherapy is a promising strategy to target lung tumours and to limit the induced severe systemic toxicities. Cisplatin dry powder for inhalation (CIS-DPI) was tested as an innovative way to deliver cisplatin locally via the pulmonary route with minimal systemic toxicities. In vivo, CIS-DPI demonstrated a dose-dependent antiproliferative activity in the M109 orthotopic murine lung tumour model and upregulated the immune checkpoint PD-L1 on lung tumour cells. Combination of CIS-DPI with the immune checkpoint inhibitor anti-PD1 showed significantly reduced tumour size, increased the number of responders and prolonged median survival over time in comparison to the anti-PD1 monotherapy. Furthermore, the CIS-DPI and anti-PD1 combination induced an intra-tumour recruitment of conventional dendritic cells and tumour infiltrating lymphocytes, highlighting an anti-tumour immune response. This study demonstrates that combining CIS-DPI with anti-PD1 is a promising strategy to improve lung cancer therapy.

Design and selection of optimal ErbB-targeting bispecific antibodies in pancreatic cancer.

The ErbB family of receptor tyrosine kinases is a primary target for small molecules and antibodies for pancreatic cancer treatment. Nonetheless, the current treatments for this tumor are not optimal due to lack of efficacy, resistance, or toxicity. Here, using the novel BiXAb™ tetravalent format platform, we generated bispecific antibodies against EGFR, HER2, or HER3 by considering rational epitope combinations. We then screened these bispecific antibodies and compared them with the parental single antibodies and antibody pair combinations. The screen readouts included measuring binding to the cognate receptors (mono and bispecificity), intracellular phosphorylation signaling, cell proliferation, apoptosis and receptor expression, and also immune system engagement assays (antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity). Among the 30 BiXAbs™ tested, we selected 3Patri-1Cetu-Fc, 3Patri-1Matu-Fc and 3Patri-2Trastu-Fc as lead candidates. The in vivo testing of these three highly efficient bispecific antibodies against EGFR and HER2 or HER3 in pre-clinical mouse models of pancreatic cancer showed deep antibody penetration in these dense tumors and robust tumor growth reduction. Application of such semi-rational/semi-empirical approach, which includes various immunological assays to compare pre-selected antibodies and their combinations with bispecific antibodies, represents the first attempt to identify potent bispecific antibodies against ErbB family members in pancreatic cancer.

Abundant genetic variability in Drosophila simulans for hybrid female lethality in interspecific crosses to Drosophila melanogaster.

Intrinsic postzygotic reproductive isolation is thought to result from the substitution of multiple harmless or beneficial genetic differences between species that are incidentally deleterious when combined in species hybrids, causing hybrid sterility or inviability. Genetic variability for hybrid sterility or inviability phenotypes is, however, rarely assessed in natural populations. Here, we assess variation for Drosophila simulans-encoded maternal factor(s) that cause lethality in D. simulans-Drosophila melanogaster F(1) hybrid females. First, we survey genetic variability in the strength of D. simulans-mediated maternal effect hybrid lethality among 37 geographic and laboratory isolates. We find abundant variability in the strength of maternal effect hybrid lethality, ranging from complete lethality to none. Second, we assess maternal effect hybrid lethality for a subset of wild isolates made heterozygous with two so-called hybrid rescue strains. The results suggest that the D. simulans maternal effect hybrid lethality involves a diversity of alleles and/or multiple loci.

Large-scale selective sweep among Segregation Distorter chromosomes in African populations of Drosophila melanogaster.

Segregation Distorter (SD) is a selfish, coadapted gene complex on chromosome 2 of Drosophila melanogaster that strongly distorts Mendelian transmission; heterozygous SD/SD(+) males sire almost exclusively SD-bearing progeny. Fifty years of genetic, molecular, and theory work have made SD one of the best-characterized meiotic drive systems, but surprisingly the details of its evolutionary origins and population dynamics remain unclear. Earlier analyses suggested that the SD system arose recently in the Mediterranean basin and then spread to a low, stable equilibrium frequency (1-5%) in most natural populations worldwide. In this report, we show, first, that SD chromosomes occur in populations in sub-Saharan Africa, the ancestral range of D. melanogaster, at a similarly low frequency (approximately 2%), providing evidence for the robustness of its equilibrium frequency but raising doubts about the Mediterranean-origins hypothesis. Second, our genetic analyses reveal two kinds of SD chromosomes in Africa: inversion-free SD chromosomes with little or no transmission advantage; and an African-endemic inversion-bearing SD chromosome, SD-Mal, with a perfect transmission advantage. Third, our population genetic analyses show that SD-Mal chromosomes swept across the African continent very recently, causing linkage disequilibrium and an absence of variability over 39% of the length of the second chromosome. Thus, despite a seemingly stable equilibrium frequency, SD chromosomes continue to evolve, to compete with one another, or evade suppressors in the genome.

Effect of PMMA Coupling Layer in Enhancing the Ultrasonic Weld Strength of Novel Room Temperature Curable Acrylic Thermoplastic to Epoxy Based Composites.

The joining of composites can be performed in an extremely short time with more energy-efficient ultrasonic welding techniques. The current research investigated the performance optimization of ultrasonic welding of carbon/Elium® composite to carbon/epoxy composite using a polymethyl methacrylate (PMMA) coupling interlayer. The weld strength was quantified by static lap shear strength (LSS) testing. A new methodology was used by creating a PMMA coupling layer on the epoxy composite adherend to achieve an improved interphase and thus enhance the weld properties. The LSS of Elium (EL)-Epoxy (EP) _0.25_0.25 was found to be 190% higher compared to that of EL-EP, confirming the effectiveness of the strategy used for creating an interlayer thermoplastic coupling layer. The time required for welding was optimized to be 2s as compared to 10 min required for adhesive bonding. Scanning electron microscopic images of epoxy and PMMA/Elium matrix interphase were observed to have a rough surface and remained largely unaffected by welding. There was an interphase change further away from the interphase to a rougher texture. There was little to no effect on the penultimate layer on the weld strength, as no interphase change could be observed after welding. Fractography investigation revealed shear cusps, matrix plastic deformation, fiber imprints, fiber pull-out, and good adhesion between matrix and fiber, features seen for configuration with maximum LSS. The current research findings present a way to join Elium® with epoxy composites that could be used in applications that require a selective strengthening, such as in sporting goods and consumer products. Furthermore, a detailed investigation is ongoing to use different filler particles and coupling layers to reach the maximum welding performance.

Behaviour of Rectangular Hollow Thin Ply Carbon Thermoset and Thermoplastic Composite Tubes Subjected to Bending.

Tubular composites are widely used in many industrial applications, and there is need to use new material and reliable manufacturing processes to improve the performance and process aspects. The current research presents a detailed study to understand the flexure response of rectangular tubular composites based on thin ply carbon fibres and Elium® resin. Another aim was to understand the failure mechanisms of novel tubular thermoplastic composite systems and carry out a baseline comparison with Epoxy-based tubular systems. In the current research, a bladder-assisted resin transfer moulding process was used to manufacture hollow thermoplastic composite tubes, and the bending behaviour of thin ply carbon (TPC) composite parts with novel Elium® (EL) and Epoxy (EP) resin as the matrix material was studied using a detailed experimental study. A testing method with optimized support span and a saddle was used to carry out three-point bending tests on the tubular composite structures. The TPC/EL composite tubes have shown 10% higher bending strength, with a noticeable increase in deformation due the presence of extended plasticity attributes for acrylic Elium resin. Failure mechanisms studied with the detailed microscopic investigation have shown severe catastrophic failure for epoxy-based composite tubes; however, acrylic Elium®-based composite tubes have shown different damage modes such as fibre splitting, resin infragmentation, and fibre resin-interfacial cracking.

On the Mode I and Mode II Delamination Characteristics and Surface Morphological Aspects of Composites with Carbon-Thermoplastic Hybrid Fabrics and Innovative Liquid Thermoplastic Resin.

In the current research, the delamination behavior under Mode I and Mode II loading for the hybrid carbon-thermoplastic fabrics in conjunction with novel liquid thermoplastic acrylic Elium® resin processable at ambient conditions was studied. The experimentation by incorporating doublers methodology, studying the performance under Mode I and Mode II loading, and understanding failure mechanisms using surface morphological fractography is deliberated. Hybrid Carbon-Ultra-high molecular weight polyethylene (UHMWPP)/Elium® composite has shown a 22.81% higher GIC and a 22.2% higher GIIC than Carbon-UHMWPP/Epoxy composite. On the contrary, the Carbon_Ultra-high molecular weight polypropylene (UHMWPE)/Elium® has shown an 11.11% higher Mode I critical energy release rate (GIC) and a 7.58% higher Mode II critical energy release rate (GIIC) than Carbon_UHMWPE/Epoxy composite. Hybrid fiber reinforced thermoplastic composites have shown severe plastic deformation of the matrix, rough fracture surface, and micro-cracks on the de-bonding surface, extensive fiber bridging, and crack branching which contributed to the improvement in the delamination behavior. Hybrid fiber architecture is also found to be detrimental by inducing crack arresting mechanisms including the tortuous crack path and the resin-rich pockets path due to the mismatch of the size of the fiber yarns.

When a pH-triggered nanopatterned shape transition drives the wettability of a hierarchically self-organized film: A bio-inspired effect of "sea Anemone".

HYPOTHESIS: Hierarchically structured surfaces including sensitive materials presents the advantage to exalt wettability variation due to the combination of micro structure effect directed by Cassie Baxter and/or Wenzel behaviour which is tuned by the surface energy variation of sensitive polymer films. EXPERIMENTS: Herein is reported the synthesis and the hierarchical structuration of a pH sensitive diblock copolymer P(S-stat-MMA)-b-P4VP with a pH-sensitive Poly 4-vinylpyridine P4VP block. Applying the Breath Figure method casting (minute time scale process), this diblock copolymer allows to obtain a micro porous honeycomb film while a wall nano-structuration due to self-assembly of diblock copolymer is observed. FINDINGS: The pH-triggered wettability is studied and correlated with the morphology evolution of P4VP nano-domains investigated by AFM in a liquid cell. Indeed, a nano-dots to nano-rings/donuts transition is highlighted when decreasing the pH below the pKa of the P4VP. This nano "sea Anemone" shape transition induces the macroscopic changes of the wettability of a hierarchically self-organized honeycomb film, explained by the protonation of P4VP chains inducing electrostatic repulsion and then hydrophilic surface.

Optimizing Bladder Resin Transfer Molding Process to Manufacture Complex, Thin-Ply Thermoplastic Tubular Composite Structures: An Experimental Case Study.

The bladder molding process is primarily used in sporting applications but mostly with prepregs. Bladder-Assisted Resin Transfer Molding (B-RTM) presents the tremendous potential to automate and mass produce the complex hollow-composite profiles. Thin-ply, non-crimp fabrics (NCFs) provide excellent mechanical, fracture toughness, and vibration damping properties on top of the weight saving it offers to a final product. However, these fiber architectures are difficult to inject due to the resistance they provide for the polymer flow using the liquid injection process. Therefore, it is mandatory to optimize the process parameters to reduce the time for injection and simultaneously achieve better consolidation. This work presents a first, detailed, experimental case study to successfully inject a low-permeability, thin-ply, complex, thermoplastic tubular structure, and the effect of process parameters, boundary conditions, the associated manufacturing challenges, and proposed solutions are deliberated in this paper.