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Abstract Background Emphysema influences the appearance of lung tissue in computed tomography (CT). We evaluated whether this affects lung nodule detection by artificial intelligence (AI) and human readers (HR). Methods Individuals were selected from the “Lifelines” cohort who had undergone low-dose chest CT. Nodules in individuals without emphysema were matched to similar-sized nodules in individuals with at least moderate emphysema. AI results for nodular findings of 30–100 mm3 and 101–300 mm3 were compared to those of HR; two expert radiologists blindly reviewed discrepancies. Sensitivity and false positives (FPs)/scan were compared for emphysema and non-emphysema groups. Results Thirty-nine participants with and 82 without emphysema were included (n = 121, aged 61 ± 8 years (mean ± standard deviation), 58/121 males (47.9%)). AI and HR detected 196 and 206 nodular findings, respectively, yielding 109 concordant nodules and 184 discrepancies, including 118 true nodules. For AI, sensitivity was 0.68 (95% confidence interval 0.57–0.77) in emphysema versus 0.71 (0.62–0.78) in non-emphysema, with FPs/scan 0.51 and 0.22, respectively (p = 0.028). For HR, sensitivity was 0.76 (0.65–0.84) and 0.80 (0.72–0.86), with FPs/scan of 0.15 and 0.27 (p = 0.230). Overall sensitivity was slightly higher for HR than for AI, but this difference disappeared after the exclusion of benign lymph nodes. FPs/scan were higher for AI in emphysema than in non-emphysema (p = 0.028), while FPs/scan for HR were higher than AI for 30–100 mm3 nodules in non-emphysema (p = 0.009). Conclusions AI resulted in more FPs/scan in emphysema compared to non-emphysema, a difference not observed for HR. Relevance statement In the creation of a benchmark dataset to validate AI software for lung nodule detection, the inclusion of emphysema cases is important due to the additional number of FPs. Key points • The sensitivity of nodule detection by AI was similar in emphysema and non-emphysema. • AI had more FPs/scan in emphysema compared to non-emphysema. • Sensitivity and FPs/scan by the human reader were comparable for emphysema and non-emphysema. • Emphysema and non-emphysema representation in benchmark dataset is important for validating AI. Graphical Abstract

AbstractBackground Light therapy (LT) for Seasonal Affective Disorders (SAD) has been a well-known and effective treatment for 40 years. The psychiatric university clinic of Groningen, the Netherlands was an early adopter and started research and treatment of SAD in 1987. Research projects on mechanisms, the role of the circadian system, treatment optimization, and investigating new areas for the effects of light treatment have been carried out ever since, leading to a widespread interest across the country.Objective To provide an overview and description of the historical development of LT for mental disorders in the Netherlands.Methods A non-systematic, review of research on light treatment for mental problems in the Netherlands, published since 1987 was conducted.Results The fields of LT and chronotherapy are strongly based in the scientific interests of both chrono-biologists and therapists in the Netherlands. LT has shown effectiveness in treating mood disorders. Likewise, results for other mental disorders have shown some promise, but so far, the outcomes are not always unequivocal and have not always been based on robust data. Ongoing research is discussed.Conclusions LT, and in addition exposure to the right light at the right time is an important issue in mental health. Over the past 3 decades research on light and LT in the Netherlands has become well established and is still growing.

Age-related loss of vestibular function and hearing are common disorders that arise from the loss of function of the inner ear and significantly decrease quality of life. The underlying pathophysiological mechanisms are poorly understood and difficult to investigate in humans. Therefore, our study examined young (1.5-month-old) and old (24-month-old) C57BL/6 mice, utilizing physiological, histological, and transcriptomic methods. Vestibular sensory-evoked potentials revealed that older mice had reduced wave I amplitudes and delayed wave I latencies, indicating reduced vestibular function. Immunofluorescence and image analysis revealed that older mice exhibited a significant decline in type I sensory hair cell density, particularly in hair cells connected to dimorphic vestibular afferents. An analysis of gene expression in the isolated vestibule revealed the upregulation of immune-related genes and the downregulation of genes associated with ossification and nervous system development. A comparison with the isolated cochlear sensorineural structures showed similar changes in genes related to immune response, chondrocyte differentiation, and myelin formation. These findings suggest that age-related vestibular hypofunction is linked to diminished peripheral vestibular responses, likely due to the loss of a specific subpopulation of hair cells and calyceal afferents. The upregulation of immune- and inflammation-related genes implies that inflammation contributes to these functional and structural changes. Furthermore, the comparison of gene expression between the vestibule and cochlea indicates both shared and distinct mechanisms contributing to age-related vestibular and hearing impairments. Further research is necessary to understand the mechanistic connection between inflammation and age-related balance and hearing disorders and to translate these findings into clinical treatment strategies.

The body is at the heart of critical and phenomenological concerns, yet it is the soul that is increasingly under pressure. As we are being stripped of our structures of commonality, we need a renewed concept of political spirituality. My aim is to enrich Simondon’s concept of spirituality as transindividuality through Souriau’s transmodal architectonics. My argument proceeds in two steps: (i) I emphasize the precarious and communal modality of «having a soul», defining it as a possession without ownership and demonstrating its inseparability from the problems of intensive variation and discontinuity. (ii) I then argue that Souriau is inspired by Leibniz’s disjunction between the ontic soul and the relational body, which holds the key to an account of spiritual commitment that exceeds the union of corporeal and psychical existences insofar as it invents a new common use for them.

Although aminoglycosides are frequently prescribed to neonates and children, the ability to reach effective and safe target concentrations with the currently used dosing regimens remains unclear. This study aims to evaluate the target attainment of the currently used dosing regimens for gentamicin in neonates and children. We conducted a retrospective single-center cohort study in neonates and children receiving gentamicin between January 2019 and July 2022, in the Beatrix Children’s Hospital. The first gentamicin concentration used for therapeutic drug monitoring was collected for each patient, in conjunction with information on dosing and clinical status. Target trough concentrations were ≤1 mg/L for neonates and ≤0.5 mg/L for children. Target peak concentrations were 8–12 mg/L for neonates and 15–20 mg/L for children. In total, 658 patients were included (335 neonates and 323 children). Trough concentrations were outside the target range in 46.2% and 9.9% of neonates and children, respectively. Peak concentrations were outside the target range in 46.0% and 68.7% of neonates and children, respectively. In children, higher creatinine concentrations were associated with higher gentamicin trough concentrations. This study corroborates earlier observational studies showing that, with a standard dose, drug concentration targets were met in only approximately 50% of the cases. Our findings show that additional parameters are needed to improve target attainment.

Arbuscular mycorrhizal (AM) fungi, symbionts of most land plants, increase plant fitness in metal contaminated soils. To further understand the mechanisms of metal tolerance in the AM symbiosis, the expression patterns of the maize Heavy Metal ATPase (HMA) family members and the ionomes of non-mycorrhizal and mycorrhizal plants grown under different Cu supplies were examined. Expression of ZmHMA5a and ZmHMA5b, whose encoded proteins were predicted to be localized at the plasma membrane, was up-regulated by Cu in non-mycorrhizal roots and to a lower extent in mycorrhizal roots. Gene expression of the tonoplast ZmHMA3a and ZmHMA4 isoforms was up-regulated by Cu-toxicity in shoots and roots of mycorrhizal plants. AM mitigates the changes induced by Cu toxicity on the maize ionome, specially at the highest Cu soil concentration. Altogether these data suggest that in Cu-contaminated soils, AM increases expression of the HMA genes putatively encoding proteins involved in Cu detoxification and balances mineral nutrient uptake improving the nutritional status of the maize plants.

Pesticide resistance in insects is an example of adaptive evolution occurring in pest species and is driven by the artificial introduction of pesticides. The diamondback moth (DBM), Plutella xylostella (Lepidoptera: Plutellidae), has evolved resistance to various insecticides. Understanding the genetic changes underpinning the resistance to pesticides is necessary for the implementation of pest control measures. We sequenced the genome of six resistant and six susceptible DBM individuals separately and inferred the genomic regions of greatest divergence between strains using FST and θπ. Among several genomic regions potentially related to insecticide resistance, CYP6B6-like was observed with significant divergence between the resistant and susceptible strains, with a missense mutation located near the substrate recognition site (SRS) and four SNPs in the promoter. To characterize the relative effects of directional selection via insecticide tolerance (‘strain’) as compared to acute exposure to insecticide (‘treatment’), four pairwise comparisons were carried out between libraries to determine the differentially expressed genes. Most resistance-related differentially expressed genes were identified from the comparison of the strains and enriched in pathways for exogenous detoxification including cytochrome P450 and the ABC transporter. Further confirmation came from the weighted gene co-expression network analysis, which indicated that genes in the significant module associated with chlorantraniliprole resistance were enriched in pathways for exogenous detoxification, and that CYP6B6-like represented a hub gene in the “darkred” module. Furthermore, RNAi knock-down of CYP6B6-like increases P. xylostella sensitivity to chlorantraniliprole. Our study thus provides a genetic foundation underlying selection for pesticide resistance and plausible mechanisms to explain fast evolved adaptation through genomic divergence and altered gene expression in insects.

Age-related hearing loss (ARHL) or presbycusis is a prevalent condition associated with social isolation, cognitive impairment, and dementia. Age-related changes in the cochlea, the auditory portion of the inner ear, are the primary cause of ARHL. Unfortunately, there are currently no pharmaceutical approaches to treat ARHL. To examine the biological processes underlying age-related changes in the cochlea and identify candidate drugs for rapid repurposing to treat ARHL, we utilized bulk RNA sequencing to obtain transcriptomes from the functional substructures of the cochlea—the sensorineural structures, including the organ of Corti and spiral ganglion neurons (OC/SGN) and the stria vascularis and spiral ligament (SV/SL)—in young (6-week-old) and old (2-year-old) C57BL/6 mice. Transcriptomic analyses revealed both overlapping and unique patterns of gene expression and gene enrichment between substructures and with ageing. Based on these age-related transcriptional changes, we queried the protein products of genes differentially expressed with ageing in DrugBank and identified 27 FDA/EMA-approved drugs that are suitable to be repurposed to treat ARHL. These drugs target the protein products of genes that are differentially expressed with ageing uniquely in either the OC/SGN or SV/SL and that interrelate diverse biological processes. Further transcriptomic analyses revealed that most genes differentially expressed with ageing in both substructures encode protein products that are promising drug target candidates but are, nevertheless, not yet linked to approved drugs. Thus, with this study, we apply a novel approach to characterize the druggable genetic landscape for ARHL and propose a list of drugs to test in pre-clinical studies as potential treatment options for ARHL.

Background: Wetlands in Neotropics harbor high fungal diversity, including arbuscular mycorrhizal fungi (AMF) and dark septate endophytes (DSE). This study describes the interaction of plant roots with AMF and DSE in a freshwater wetland belonging to a hotspot of biodiversity. Hypothesis: Differential root colonization between arbuscular mycorrhizal and dark septate endophyte fungi is influenced by plant species and abiotic conditions in a freshwater wetland. Studied species: Plant species colonized by arbuscular mycorrhizal and dark septate endophyte fungi. Methods: Properties of soils and the water column, floristic composition, root colonization by AMF and DSE, and molecular identification of AMF inside roots were studied. Results: Soils were Gleysol and flooded during the rainy season. Most of identified plant species were herbaceous, with Cyperus articulatus and Mimosa pigra as the dominant species. Seven of 8 analyzed plant species exhibited differential co-colonization between AMF and DSE. Repeated sampling for one year under flooding/dry conditions demonstrated that C. articulatus and M. pigra were mainly associated with DSE and AMF, respectively. A positive correlation between dissolved O2 in the water column and fungal colonization was observed in C. articulatus. Glomerales and Archaeosporales were molecularly identified inside roots containing arbuscules of M. pigra. Conclusions: Findings highlight differential coexistence between AMF and DSE in plant roots; fungal colonization was influenced by flooding/dry conditions in a neotropical wetland; the community of AMF inside arbusculated roots of M. pigra includes at least four clades.

Abstract Background Botrytis cinerea, a necrotrophic pathogenic fungus, attacks many crops including potato and tomato. Major genes for complete resistance to B. cinerea are not known in plants, but a few quantitative trait loci have been described in tomato. Loss of function of particular susceptibility (S) genes appears to provide a new source of resistance to B. cinerea in Arabidopsis. Results In this study, orthologs of Arabidopsis S genes (DND1, DMR6, DMR1 and PMR4) were silenced by RNAi in potato and tomato (only for DND1). DND1 well-silenced potato and tomato plants showed significantly reduced diameters of B. cinerea lesions as compared to control plants, at all-time points analysed. Reduced lesion diameter was also observed on leaves of DMR6 silenced potato plants but only at 3 days post inoculation (dpi). The DMR1 and PMR4 silenced potato transformants were as susceptible as the control cv Desiree. Microscopic analysis was performed to observe B. cinerea infection progress in DND1 well-silenced potato and tomato leaves. A significantly lower number of B. cinerea conidia remained attached to the leaf surface of DND1 well-silenced potato and tomato plants and the hyphal growth of germlings was hampered. Conclusions This is the first report of a cytological investigation of Botrytis development on DND1-silenced crop plants. Silencing of DND1 led to reduced susceptibility to Botrytis, which was associated with impediment of conidial germination and attachment as well as hyphal growth. Our results provide new insights regarding the use of S genes in resistance breeding.

Aim: To improve knowledge of arbuscular fungal communities for a sustainable management in vineyards. Methods and results: In 16 plots across Burgundy under contrasted soil properties and agricultural practices, we assessed arbuscular mycorrhizal fungal (AMF) diversity in vine roots, using pyrosequencing of ribosomal Internal Transcribed Spacers (ITS). AMF sequences could be retrieved from all plots across Burgundy, both in organic and in conventional vineyards with high chemical inputs. Sequences from the survey were almost exclusively affiliated to molecular taxa in the Glomerales, including six “core species” found in all plots, corresponding to 77% of all sequences, suggesting a relatively low species diversity in vine roots. A large part of the molecular taxa had no close similarity to previously-reported sequences. Conclusion: AMF diversity observed in vine roots was relatively low and a significant proportion of molecular taxa shared between the sites. Nevertheless, some differences in the AMF community composition were observed between the plots. Significance and impact of the study: This is the first large-scale study of AMF diversity in French vineyards using high-throughput sequencing, which will contribute to a better understanding of ecology of these fungi in vine roots, thus providing essential knowledge for future applications in sustainable agriculture in vineyards

Plants interact with microbes whose ultimate aim is to exploit plant carbohydrates for their reproduction. Plant–microbe interactions (PMIs) are classified according to the nature of their trophic exchanges: while mutualistic microbes trade nutrients with plants, pathogens unilaterally divert carbohydrates. The early responses following microbe recognition and the subsequent control of plant sugar distribution are still poorly understood. To further decipher PMI functionality, we used tobacco cells treated with microbial molecules mimicking pathogenic or mutualistic PMIs, namely cryptogein, a defense elicitor, and chitotetrasaccharide (CO4), which is secreted by mycorrhizal fungi. CO4 was perceived by tobacco cells and triggered widespread transient signaling components such as a sharp cytosolic Ca2+ elevation, NtrbohD-dependent H2O2 production, and MAP kinase activation. These CO4-induced events differed from those induced by cryptogein, i.e., sustained events leading to cell death. Furthermore, cryptogein treatment inhibited glucose and sucrose uptake but not fructose uptake, and promoted the expression of NtSUT and NtSWEET sugar transporters, whereas CO4 had no effect on sugar uptake and only a slight effect on NtSWEET2B expression. Our results suggest that microbial molecules induce different signaling responses that reflect microbial lifestyle and the subsequent outcome of the interaction.

Expression profiling of two paralogous arbuscular mycorrhizal (AM)-specific blue copper-binding gene (MtBcp1a and MtBcp1b) isoforms was performed by real-time quantitative polymerase chain reaction in wild-type Medicago truncatula Jemalong 5 (J5) during the mycorrhizal development with Glomus intraradices for up to 7 weeks. Time-course analysis in J5 showed that expression of both MtBcp1 genes increased continuously and correlated strongly with the colonization intensity and arbuscule content. MtPT4, selected as a reference gene of the functional plant-fungus association, showed a weaker correlation to mycorrhizal development. In a second experiment, a range of mycorrhizal mutants of the wild-type J5 was assessed. Strictly AM-penetration-defective TRV25-C and TRV25-D (dmi3, Mtsym13), hypomycorrhizal TR25 and TR89 (dmi2, Mtsym2) mutants, and a hypermycorrhizal mutant TRV17 (sunn, Mtsym12) were compared with J5 3 and 7 weeks after inoculation. No MtBcp1 transcripts were detected in the mutants blocked at the appressoria stage. Conversely, TR25, TR89, and J5 showed a gradual increase of the expression of both MtBcp1 genes in 3- and 7-week-old plants, similar to the increase in colonization intensity and arbuscule abundance. The strong correlation between the expression level of AM-specific blue copper-binding protein-encoding genes and AM colonization may imply a basic role in symbiotic functioning for these genes, which may serve as new molecular markers of arbuscule development in M. truncatula.

To gain further insight into the role of the plant genome in arbuscular mycorrhiza (AM) establishment, we investigated whether symbiosis-related plant genes affect fungal gene expression in germinating spores and at the appressoria stage of root interactions. Glomus intraradices genes were identified in expressed sequence tag libraries of mycorrhizal Medicago truncatula roots by in silico expression analyses. Transcripts of a subset of genes, with predicted functions in transcription, protein synthesis, primary or secondary metabolism, or of unknown function, were monitored in spores and germinating spores and during interactions with roots of wild-type or mycorrhiza-defective (Myc–) mutants of M. truncatula. Not all the fungal genes were active in quiescent spores but all were expressed when G. intraradices spores germinated in wild-type M. truncatula root exudates or when appressoria or arbuscules were formed in association with wild-type M. truncatula roots. Most of the fungal genes were upregulated or induced at the stage of appressorium development. Inactivation of the M. truncatula genes DMI1, DMI2/MtSYM2, or DMI3/MtSYM13 was associated with altered fungal gene expression (nonactivation or inhibition), modified appressorium structure, and plant cell wall responses, providing first evidence that cell processes modified by symbiosis-related plant genes impact on root interactions by directly modulating AM fungal activity.

A mobilização do solo reduz a taxa de colonização por micorrizas arbusculares (MA) uma vez que ao provocar a disrupção do micélio extraradicular, faz com que a colonização seja preferencialmente iniciada por fontes de inoculo de crescimento mais lento. Em solos pouco perturbados, o aumento da taxa de colonização micorrízica é normalmente associado, embora nem sempre, a uma vantagem comparativa destas plantas numa fase inicial do crescimento. No sentido de potenciar os benefícios proporcionados pela micorrização e numa óptica de sustentabilidade dos sistemas agrícolas, é fundamental o desenvolvimento de conhecimentos que elucidem sobre a ecologia funcional das MA nestes sistemas. O trabalho desenvolvido em condições de campo no Alentejo permitiu confirmar de forma clara que raízes de trigo e de triticale cultivados em sistema de sementeira directa (SD) apresentaram uma taxa de colonização micorrízica superior, em cerca de 6 vezes, quando comparadas com raízes de plantas das mesmas espécies cultivadas em sistema de mobilização tradicional (MT). Os resultados obtidos indicam também que o triticale parece ser mais micotrófico que o trigo. Para uma melhor compreensão das implicações desta situação nas plantas desenvolveram-se ensaios em vasos. A perturbação do solo induzida pela mobilização foi reproduzida através da crivagem do solo por um crivo de 4mm. Vários parâmetros de crescimento da planta e de colonização micorrízica foram avaliados. Após 4 ciclos de 3 semanas de cultura de trigo com indução diferencial de estrutura ao nível do solo, todos os parâmetros de colonização micorrízica foram significativamente afectados. A colonização arbuscular, vesicular e por hifas foi maior em solo não perturbado. Presentemente esta metodologia de ciclos de perturbação do solo está a ser usada para avaliar diferentes aspectos da micorrização como sejam a sobrevivência de inoculo ao longo do Verão e a sua capacidade para gerar novas colonizações no período cultural. Com o objectivo de avaliar a diversidade dos Glomeromycota presentes no campo de ensaios em estudo, sujeito aos dois tipos de mobilização do solo (SD e MT), foi usada a técnica de amplificação de sequências de rDNA destes fungos a partir de DNA total do solo. Esta técnica permite uma avaliação abrangente, evitando a morosidade e complexidade da abordagem clássica através de culturas armadilha. No total foram analisadas 87 sequencias, provenientes de solo perturbado e não perturbado, e encontrados 11 tipos ribosomais. Considerando as diferenças de frequência dos tipos ribosomais presentes em cada tipo de solo, os resultados parecem confirmar que os fungos micorrízicos arbusculares são diferencialmente susceptíveis à perturbação do solo, não só em termos de diversidade como ao nível da estrutura da comunidade.Soil tillage may markedly reduce the rate of arbuscular mycorrhiza (AM) establishment by breaking up the living AM fungal mycelium in the soil. In no till or reduced till management, this mycelium can allow earlier AM formation. Work under field conditions in a Mediterranean climate clearly confirmed that wheat plants cultivated under no-till system had a 6 fold greater mycorrhizal colonization than those grown using a conventional tillage system. Pot experiments were initiated to determine the benefit of the timing of colonization on plants. Soil disturbance induced by tillage practices was simulated by passing the soil through a 4 mm sieve at the start of each successive period of 3 weeks plant growth cycles. After 4 cycles of plant growth (wheat), significant effects in all colonization parameters were detected. Arbuscular, vesicular and hyphal colonization were clearly higher in undisturbed soil. To gain a global overview of the diversity of Glomeromycota under the 2 cultivation systems in the experimental field, rDNA sequences from the fungi have been amplified successfully from DNA extracted directly from field soil. In total 87 sequences were analysed, half from each kind of soil (undisturbed and disturbed). Based on differences observed in the frequency of the ribotypes present in soils under different tillage treatments, the results support the view that AMF are differently vulnerable to soil disturbance, not only in terms of diversity, but also in terms of the community structure.