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Fabrication of catalytically active electrodes by electrodeposition is attractive due to its in situ nature, easy controllability, and large-scale operation capability. Most recently, modifying the electrodes with phosphate ligands through electrodepositing electrode materials has shown promising results in improving the kinetics of some reactions. However, it is unclear how the presence of phosphate anions affects the electrodeposition process and functions in catalyzing reactions. Here, we report a systematic study on electrodeposition of Cu in the presence of phosphate anions. The phosphate anions form a complex with free Cu(ii) cations, competing with the electrodeposition process. The competition between the two processes results in an insufficient supply of free Cu(ii) for electrodeposition, especially at the diffusion layer. This is evidenced by the calculation of free Cu(ii) concentration and the electrodeposition current at identical applied potentials. We also found that the electrodeposition of Cu in the presence of phosphate generates Cu-oxyo/hydroxyo-phosphate species on the deposited copper surface. The modified electrodes with phosphate species exhibit higher selectivity for HCOOH formation (faradaic efficiency ∼80%) from the electrochemical reduction of CO2 as compared with Cu foil (faradaic efficiency ∼33%). The effect of phosphate ligands promoting HCOOH selectivity is further verified by stripping off the ligands and regenerating the ligands.

Abstract Background Elevated mammographic density (MD) for a woman’s age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD). Methods ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35–85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest. Results Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (β: − 0.05, 95% confidence interval (CI): − 0.07, − 0.03) and √DA (β: − 0.08, 95% CI: − 0.12, − 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (β:0.06, 95% CI:0.03, 0.10) and √DA (β:0.06, 95% CI:0.02, 0.10), and lower √NDA (β: − 0.06, 95% CI: − 0.11, − 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD. Conclusions Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk.

Abstract People with diabetes have an increased cardiovascular risk and a poorer outcome after myocardial infarction (MI). However, the exact underlying mechanisms are still unclear, as is the question of which non-invasive measures could be used to predict the altered risk for the patient at early stages of the disease and adapt personalized treatment. Here, we used a holistic magnetic resonance approach to monitor longitudinally not only the main target heart, but also liver, peripheral/skeletal muscle, bone marrow, and hematopoiesis during disease development and subsequent MI. In prediabetic mice, we found a strong accumulation of lipids in all organs which preceded even a significant whole-body weight gain. Intramyocellular lipids (IMCLs) were most sensitive to reveal in vivo very early alterations in tissue properties during the prediabetic state. Subsequent induction of MI led to a persistent impairment of contractile function in septal/posterior segments of prediabetic hearts which correlated with their lipid load prior MI. At the same time, prediabetic cardiomyocytes exhibited sarcomere function at its limit resulting in overload and lower compensatory contractility of the healthy myocardium after MI. In summary, we identified IMCLs as very early marker in murine prediabetes and together with the cardiac lipid load as predictive for the functional outcome after MI.

One of the most challenging aspects of X-ray research is the delivery of liquid sample flows into the soft X-ray beam. Currently, cylindrical microjets are the most commonly used sample injection systems for soft X-ray liquid spectroscopy. However, they suffer from several drawbacks, such as complicated geometry due to their curved surface. In this study, we propose a novel 3D-printed nozzle design by introducing microscopic flat sheet jets that provide micrometre-thick liquid sheets with high stability, intending to make this technology more widely available to users. Our research is a collaboration between the EuXFEL and MAX IV research facilities. This collaboration aims to develop and refine a 3D-printed flat sheet nozzle design and a versatile jetting platform that is compatible with multiple endstations and measurement techniques. Our flat sheet jet platform improves the stability of the jet and increases its surface area, enabling more precise scanning and differential measurements in X-ray absorption, scattering, and imaging applications. Here, we demonstrate the performance of this new arrangement for a flat sheet jet setup with X-ray photoelectron spectroscopy, photoelectron angular distribution, and soft X-ray absorption spectroscopy experiments performed at the photoemission endstation of the FlexPES beamline at MAX IV Laboratory in Lund, Sweden.

Recent phylogenetic studies in Himalayan lazy toads of the genus Scutiger Theobald, 1868 revealed the presence of genetically deeply divergent lineages. The taxonomy of S. nepalensis sensu lato was re-assessed based on museum material considering molecular and morphological data. The results strongly support the recognition of a new species, S. kanjiroba sp. nov. distributed along the Nepalese Kanjiroba massif. It is further shown that S. sikimmensis has an apparently much more restricted distribution range than previously thought. The frequent misidentification of Scutiger across large areas of the Himalaya-Tibet area highlights the significance of careful taxonomic evaluation of collection material and the need for the direct morphological comparison of closely related species when describing new species.

OBJECTIVES: Etiological factors of testicular germ cell tumors (TGCT) remain largely unknown, but a causal role of occupational exposures to solvents has been suggested. Previous studies analyzing these exposures reported discordant results, potentially related to exposure assessment methods. The aim of this study was to investigate the role of occupational exposure to solvents on the risk of developing TGCT among young men. METHODS: This study examined occupational exposures to solvents and TGCT risk based on the lifetime work histories of 454 cases and 670 controls, aged 18–45 years, of the French national TESTIS case–control study. Solvent exposure was estimated using: (i) exposure assignment by job-exposure matrix (JEM) and (ii) JEM combined with self-reported exposure data from specific questionnaires (SQ) and expert assessment (EA). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. RESULTS: Both approaches (JEM and JEM+SQ+EA) showed a consistent association between TGCT and trichloroethylene exposure (exposed versus not exposed; JEM=OR 1.80 [95% confidence interval (CI) 1.12–2.90] and JEM+SQ+EA= OR 2.59 (95% CI 1.42–4.72). Both approaches also observed positive associations with ketone esters and fuels & petroleum-based solvents. CONCLUSION: The results suggest that some organic solvents might be involved in the pathogenesis of TGCT among occupationally exposed men. The combined use of JEM+SQ+EA seemed to limit misclassification by considering individual exposure variability and is, therefore, an appealing approach to assess occupational exposures in epidemiological studies.

In the context of open science, universities, research-performing and funding organizations and authorities worldwide are moving towards more responsible research assessment (RRA). In 2022, the European Coalition for Advancing Research Assessment (CoARA) published an agreement with ten commitments, including the recognition of the “diversity of contributions to, and careers in, research”, the “focus on qualitative evaluation for which peer review is central, supported by responsible use of quantitative indicators”, and the “abandon (of) inappropriate uses in research assessment of journal- and publication-based metrics”. Research assessment (RA) is essential for research of the highest quality. The transformation of assessment indicators and procedures directly affects the underlying research information management infrastructures (also called current research information systems) which collect and store metadata on research activities and outputs. This entry investigates the impact of RRA on these systems, on their development and implementation, their data model and governance, including digital ethics.

Abstract The main protease (Mpro) of SARS-CoV-2 is critical for viral function and a key drug target. Mpro is only active when reduced; turnover ceases upon oxidation but is restored by re-reduction. This suggests the system has evolved to survive periods in an oxidative environment, but the mechanism of this protection has not been confirmed. Here, we report a crystal structure of oxidized Mpro showing a disulfide bond between the active site cysteine, C145, and a distal cysteine, C117. Previous work proposed this disulfide provides the mechanism of protection from irreversible oxidation. Mpro forms an obligate homodimer, and the C117-C145 structure shows disruption of interactions bridging the dimer interface, implying a correlation between oxidation and dimerization. We confirm dimer stability is weakened in solution upon oxidation. Finally, we observe the protein’s crystallization behavior is linked to its redox state. Oxidized Mpro spontaneously forms a distinct, more loosely packed lattice. Seeding with crystals of this lattice yields a structure with an oxidation pattern incorporating one cysteine-lysine-cysteine (SONOS) and two lysine-cysteine (NOS) bridges. These structures further our understanding of the oxidative regulation of Mpro and the crystallization conditions necessary to study this structurally.

Abstract Anthropogenic activities increase the level of dissolved heavy metals in some tropical near‐shore environments threatening reef ecosystems. The skeleton of stony corals like Porites species potentially provides a high‐resolution geochemical archive for past heavy metal concentrations, with potentially century long records revealing baseline values before large‐scale human disturbance. However, few data exist for heavy metal partitioning into coral skeleton aragonite. To address this, culturing experiments exposing Porites lobata and Porites lichen to a mixture of dissolved Cr, Mn, Ni, Cu, Zn, Ag, Cd, Sn, Hg, and Pb over a wide concentration range have been performed. Water samples were taken frequently to monitor changes in the heavy metal concentration. Laser ablation ICP‐MS measurements of the coral aragonite revealed metal concentrations that were positively correlated with Cr, Mn, Ni, Zn, Ag, Cd, and Pb concentrations in seawater. The DTE values for most metals appear dependent on the seawater metal content, approximating a power law, and therefore stabilize at higher seawater metal/Ca ratios. The partitioning of Pb into the coral skeleton is a notable exception, with DPb being stable around 2 to 1 across a large range of “natural” to highly polluted seawater Pb concentrations. This and the general agreement with partition coefficients estimated by previous work suggests that the reconstruction of the heavy metal concentration in seawater for ecosystem monitoring is possible. However, the high variability within and between coral colonies requires further study and suggests that multiple records from multiple coral colonies should be combined to obtain robust reconstructions.

This article presents the results of a qualitative analysis of the use of the HAL platform by research laboratories. The analysis is based on semi-directive interviews with representatives from 50 laboratories affiliated to the ten Udice research universities. It focuses on the function that HAL fulfils for the laboratories, on its added value for their operation and their development. In particular, we are questioning the purposes of the use of HAL by the laboratories, the use of internal and external tools, and the trajectories of practices. We discuss the results from three angles: the discourses and communities of practice in the laboratories; the scope and challenges of the systems put in place by the laboratories upstream and downstream of HAL; and the transformation of HAL from a platform for self-archiving and direct scientific communication to an infrastructure for monitoring and evaluating scientific performance. This is the first in a series of three articles from the HAL/LO project.

Abstract Background Double-lumen tubes (DLTs) are the preferred device for lung isolation. Conventional DLTs (cDLT) need a bronchoscopic position control. Visualisation of correct DLT positioning could be facilitated by the use of a video double-lumen tube (vDLT). During the SARS-CoV-2-pandemic, avoiding aerosol-generation was suggesting using this device. In a large retrospective series, we report both general and pandemic related experiences with the device. Methods All anesthesia records from patients aged 18 years or older undergoing surgery from April 1st, 2020 to December 31st, 2021 in the department of thoracic surgery requiring intraoperative lung isolation were analyzed retrospectively. Results During the investigation period 343 left-sided vDLTs (77.4%) and 100 left-sided cDLTs (22.6%) were used for one lung ventilation. In the vDLT group bronchoscopy could be reduced by 85.4% related to the cDLT group. Additional bronchoscopy to reach or maintain correct position was needed in 11% of the cases. Other bronchoscopy indications occured in 3.6% of the cases. With cDLT, in 1% bronchoscopy for other indications than conforming position was observed. Conclusions The Ambu® VivaSight™ vDLT is an efficient, easy-to-use and safe airway device for the generation of one lung ventilation in patients undergoing thoracic surgery. The vDLT implementation was achieved easily with full interchangeability to the left-sided cDLT. Using the vDLT can reduce the need for aerosol-generating bronchoscopic interventions by 85.4%. Continuous video view to the carina enabling position monitoring of the DLT without need for bronchoscopy might be beneficial for both employee’s and patient’s safety.

OBJECTIVES: The quantitative job-exposure matrix SYN-JEM consists of various dimensions: job-specific estimates, region-specific estimates, and prior expert ratings of jobs by the semi-quantitative DOM-JEM. We analyzed the effect of different JEM dimensions on the exposure–response relationships between occupational silica exposure and lung cancer risk to investigate how these variations influence estimates of exposure by a quantitative JEM and associated health endpoints. METHODS: Using SYN-JEM, and alternative SYN-JEM specifications with varying dimensions included, cumulative silica exposure estimates were assigned to 16 901 lung cancer cases and 20 965 controls pooled from 14 international community-based case-control studies. Exposure–response relationships based on SYN-JEM and alternative SYN-JEM specifications were analyzed using regression analyses (by quartiles and log-transformed continuous silica exposure) and generalized additive models (GAM), adjusted for age, sex, study, cigarette pack-years, time since quitting smoking, and ever employment in occupations with established lung cancer risk. RESULTS: SYN-JEM and alternative specifications generated overall elevated and similar lung cancer odds ratios ranging from 1.13 (1st quartile) to 1.50 (4th quartile). In the categorical and log-linear analyses SYN-JEM with all dimensions included yielded the best model fit, and exclusion of job-specific estimates from SYN-JEM yielded the poorest model fit. Additionally, GAM showed the poorest model fit when excluding job-specific estimates. CONCLUSION: The established exposure–response relationship between occupational silica exposure and lung cancer was marginally influenced by varying the dimensions of SYN-JEM. Optimized modelling of exposure–response relationships will be obtained when incorporating all relevant dimensions, namely prior rating, job, time, and region. Quantitative job-specific estimates appeared to be the most prominent dimension for this general population JEM.

This work investigates the performance of the electrospray aerosol generator at the European X-ray Free Electron Laser (EuXFEL). This generator is, together with an aerodynamic lens stack that transports the particles into the X-ray interaction vacuum chamber, the method of choice to deliver particles for single-particle coherent diffractive imaging (SPI) experiments at the EuXFEL. For these experiments to be successful, it is necessary to achieve high transmission of particles from solution into the vacuum interaction region. Particle transmission is highly dependent on efficient neutralization of the charged aerosol generated by the electrospray mechanism as well as the geometry in the vicinity of the Taylor cone. We report absolute particle transmission values for different neutralizers and geometries while keeping the conditions suitable for SPI experiments. Our findings reveal that a vacuum ultraviolet ionizer demonstrates a transmission efficiency approximately seven times greater than the soft X-ray ionizer used previously. Combined with an optimized orifice size on the counter electrode, we achieve >40% particle transmission from solution into the X-ray interaction region. These findings offer valuable insights for optimizing electrospray aerosol generator configurations and data rates for SPI experiments.

Abstract Imaging the structure and observing the dynamics of isolated proteins using single-particle X-ray diffractive imaging (SPI) is one of the potential applications of X-ray free-electron lasers (XFELs). Currently, SPI experiments on isolated proteins are limited by three factors: low signal strength, limited data and high background from gas scattering. The last two factors are largely due to the shortcomings of the aerosol sample delivery methods in use. Here we present our modified electrospray ionization (ESI) source, which we dubbed helium-ESI (He-ESI). With it, we increased particle delivery into the interaction region by a factor of 10, for 26 nm-sized biological particles, and decreased the gas load in the interaction chamber corresponding to an 80% reduction in gas scattering when compared to the original ESI. These improvements have the potential to significantly increase the quality and quantity of SPI diffraction patterns in future experiments using He-ESI, resulting in higher-resolution structures.

Analyses of inequalities related to prevention and cancer therapeutics/care show disparities between countries with different economic standing, and within countries with high Gross Domestic Product. The development of basic technological and biological research provides clinical and prevention opportunities that make their implementation into healthcare systems more complex, mainly due to the growth of Personalized/Precision Cancer Medicine (PCM). Initiatives like the USA‐Cancer Moonshot and the EU‐Mission on Cancer and Europe's Beating Cancer Plan are initiated to boost cancer prevention and therapeutics/care innovation and to mitigate present inequalities. The conference organized by the Pontifical Academy of Sciences in collaboration with the European Academy of Cancer Sciences discussed the inequality problem, dependent on the economic status of a country, the increasing demands for infrastructure supportive of innovative research and its implementation in healthcare and prevention programs. Establishing translational research defined as a coherent cancer research continuum is still a challenge. Research has to cover the entire continuum from basic to outcomes research for clinical and prevention modalities. Comprehensive Cancer Centres (CCCs) are of critical importance for integrating research innovations to preclinical and clinical research, as for ensuring state‐of‐the‐art patient care within healthcare systems. International collaborative networks between CCCs are necessary to reach the critical mass of infrastructures and patients for PCM research, and for introducing prevention modalities and new treatments effectively. Outcomes and health economics research are required to assess the cost‐effectiveness of new interventions, currently a missing element in the research portfolio. Data sharing and critical mass are essential for innovative research to develop PCM. Despite advances in cancer research, cancer incidence and prevalence is growing. Making cancer research infrastructures accessible for all patients, considering the increasing inequalities, requires science policy actions incentivizing research aimed at prevention and cancer therapeutics/care with an increased focus on patients' needs and cost‐effective healthcare.

Summary: Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

Wilms tumour (WT) is the fourth leading cause of cancer death in children. Elucidating modifiable risk factors is crucial in identifying venues for primary prevention of the disease. This study aimed to review literature and synthesize environmental risk factors for WT. We conducted a systematic review and meta-analysis of epidemiological studies using PubMed, Web of Science, and Embase databases. Studies were included if they were case-control or cohort studies of children under the age of 20 years at diagnosis and reported Relative Risks (RRs) with 95 % confidence intervals (CIs). Pooled effect sizes (ES) and 95 % CIs for risk factors associated with WT were estimated using random-effects models. We included 58 eligible studies from Asia, Europe, Latin and North America, and Oceania totalling approximately10000 cases of WT diagnosed between 1953 and 2019. We confirmed an association between high birthweight ((>4000 g) ES 1.54, CI 1.20–1.97) and WT. Similarly, consistent associations were suggested for Caesarean section (ES 1.23, CI 1.07–1.42), gestational age

This paper studies private air travel frequency among the UK population using a regression analysis. The analysis accounts for a large range of independent variables, including the respondents' partners' attributes, social network dispersion and migration background. We find that both having one's best friends and/or close family members abroad is associated with more frequent flights. Partners' friends living abroad also stimulate more frequent flights. Also, partners' education level and long-standing illness or disability are, respectively, positively and negatively associated with flight frequency. First generation migration background is associated with increased flying, while higher-order generation migration background (i.e. having parents or grandparents who were born abroad) is not.

Laboratory capacities are often limited by time-consuming manual repetitive procedures rather than analysis time itself. While modern instruments are typically equipped with an autosampler, sample preparation often follows manual procedures including many labor-intensive, monotonous tasks. Particularly, for a high number of samples, well plates, and low microliter pipetting, manual preparation is error-prone often requiring repeated experiments. Sampling and sample preparation can account for greater analytical variability than instrument analysis.Repetitive tasks such as liquid handling benefit strongly from technological advances and led to the increasing applications of various automated liquid handlers (ALHs). In this review, we discuss the considerations for ALHs in the microliter range and highlight advantages and challenges when transforming from manual to automated workflows. We strongly focused on differences in liquid handling and outlined advantages due to sensor-controlled pipetting. ALHs can substantially improve costs-effectiveness and laboratory capacity. This is a consequence of increased efficiency, and throughput of laboratories while simultaneously raising data quality. Additionally, ALHs can improve safety, documentation of data, and sustainability. While automation requires careful consideration and resource demanding implementation, we believe it offers numerous advantages and can help to transform modern laboratories.

The pedelec 25 (pedal electric cycle) has established itself as a popular mode of transport, with sales rising. Unfortunately, this has also led to an increase in the number of accidents. Analyses of pedelec accidents have been carried out, but most studies are based on technical variables. Neither spatial, geographical factors, for example the terrain, nor socio-geographical aspects, such as whether an accident occurred in a tourist region, have been much addressed. However, geographical exposure can vary significantly. Therefore, we assume that spatial differences contribute to regional variations in numbers of accidents and resulting injuries associated with both bicycle types (pedelecs 25 and conventional). Thus, the aim of this paper is to determine geographical factors that influence severe accidents and to evaluate this influence. We have identified relevant geographical factors and proven their influence on two types of severity: risk of severe bicycle accidents per region (RS) and probability of severe injuries in case of accident (AS). Spatial analyses indicate that for both bicycle types, severity of accident increases in rural, mountainous or tourist regions. Regression analyses of RS provided further evidence: compactness of settlement structure (thus urbanity/rurality), share of tourists, altitude differences (only pedelecs), rate of registered motor vehicles and share of elderly population (only pedelecs) influence the risk of severe bicycle accidents per region. The influence of geographical variables tended to be greater for pedelecs. Regression analyses of AS reveal that geographical factors also have an influence on the probability of severe injuries in case of an accident.

The clinical use of the DNA damaging anticancer drug doxorubicin (DOX) is limited by irreversible cardiotoxicity, which depends on the cumulative dose. The RAS-homologous (RHO) small GTPase RAC1 contributes to DOX-induced DNA damage formation and cardiotoxicity. However, the pathophysiological relevance of other RHO GTPases than RAC1 and different cardiac cell types (i.e., cardiomyocytes, non-cardiomyocytes) for DOX-triggered cardiac damage is unclear. Employing diverse in vitro and in vivo models, we comparatively investigated the level of DOX-induced DNA damage in cardiomyocytes versus non-cardiomyocytes (endothelial cells and fibroblasts), in the presence or absence of selected RHO GTPase inhibitors. Non-cardiomyocytes exhibited the highest number of DOX-induced DNA double-strand breaks (DSB), which were efficiently repaired in vitro. By contrast, rather low levels of DSB were formed in cardiomyocytes, which however remained largely unrepaired. Moreover, DOX-induced apoptosis was detected only in non-cardiomyocytes but not in cardiomyocytes. Pharmacological inhibitors of RAC1 and CDC42 most efficiently attenuated DOX-induced DNA damage in all cell types examined in vitro. Consistently, immunohistochemical analyses revealed that the RAC1 inhibitor NSC23766 and the pan-RHO GTPase inhibitor lovastatin reduced the level of DOX-induced residual DNA damage in both cardiomyocytes and non-cardiomyocytes in vivo. Overall, we conclude that endothelial cells, fibroblasts and cardiomyocytes contribute to the pathophysiology of DOX-induced cardiotoxicity, with RAC1- and CDC42-regulated signaling pathways being especially relevant for DOX-stimulated DSB formation and DNA damage response (DDR) activation. Hence, we suggest dual targeting of RAC1/CDC42-dependent mechanisms in multiple cardiac cell types to mitigate DNA damage-dependent cardiac injury evoked by DOX-based anticancer therapy.

The Holarctic ground beetle genus Trechus Clairville, 1806, is highly diverse in the Ethiopian highlands, both in terms of species numbers and morphology. Particularly noteworthy are the extraordinarily large species of the subgenus Abyssinotus Quéinnec and Ollivier, 2021, with a body length up to 8.5 mm, that occur on Mt. Choke in northern Ethiopia. Recent, intensive field work on Mt. Choke resulted in a significantly large number of specimens that are the basis for our taxonomic revision of the species related to the giant species, T. dimorphicus Pawłowski, 2001 and T. gigas Pawłowski, 2001. We describe three new species and one new subspecies and discuss a likely interspecific hybrid that combines morphological character states of representatives of the dimorphicus and gigas subgroups of Abyssinotus. An iconography of males and females as well as photographs of the aedeagi of all the considered species are presented. The distributions of the species are detailed and knowledge of the species-specific habitat preferences is summarized. Based on the distributions and habitat specificity, a threat assessment based on the current land use pattern at Mt. Choke is provided.

Abstract Background Dermatomyositis is an idiopathic inflammatory myopathy characterised by rashes and progressive muscle weakness. The recent ProDERM (Progress in DERMatomyositis) study is the first large randomised, placebo-controlled trial to establish the efficacy and safety of intravenous immunoglobulin (IVIg) in adult patients with dermatomyositis. Objectives of this analysis were to closely examine the safety and tolerability of IVIg in patients from the ProDERM study. Methods ProDERM was a double-blind, randomised, placebo-controlled, multicentre, phase 3 study. In the first period (weeks 0–16), adults with active dermatomyositis received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label extension period (weeks 16–40), all patients received IVIg for 6 additional cycles; dose reduction (1.0 g/kg) was permitted if patients were stable. Treatment-emergent adverse events (TEAEs) were documented. Results The 95 patients enrolled were randomised to receive IVIg (N = 47) or placebo (N = 48) in the first period, with 5 switching from placebo to IVIg. Overall, 664 IVIg infusion cycles were administered. During the first period, 113 TEAEs were possibly/probably related to treatment in 30/52 patients (57.7%) receiving IVIg and 38 in 11 patients (22.9%) on placebo. Eight patients discontinued therapy due to IVIg-related TEAEs. Eight thromboembolic events (TEEs) occurred in six patients on IVIg; six in five patients were deemed possibly/probably related to IVIg. Patients with TEEs exhibited more baseline TEE risk factors than those without TEEs (2.4–15.2-fold higher). Lowering infusion rate reduced the rate of TEEs, and none occurred at the lower IVIg dose. No haemolytic transfusion reactions or deaths occurred. Conclusions Results from this study demonstrate that IVIg has a favourable safety profile for treatment of adult dermatomyositis patients and provides evidence that will help to inform treatment choice for these patients. Dermatomyositis patients receiving high-dose IVIg should be monitored for TEEs, and a low rate of infusion should be used to minimise TEE risk, particularly in those with pre-existing risk factors. Trial registration ProDERM study (NCT02728752).

Abstract To mobilize sparingly available phosphorus (P) in the rhizosphere, many plant species secrete malate to release P sorbed onto (hydr)oxides of aluminum and iron (Fe). In the presence of Fe, malate can provoke Fe over-accumulation in the root apoplast, triggering a series of events that inhibit root growth. Here, we identified HYPERSENSITIVE TO LOW P1 (HYP1), a CYBDOM protein constituted of a DOMON and a cytochrome b561 domain, as critical to maintain cell elongation and meristem integrity under low P. We demonstrate that HYP1 mediates ascorbate-dependent trans-plasma membrane electron transport and can reduce ferric and cupric substrates in Xenopus laevis oocytes and in planta. HYP1 expression is up-regulated in response to P deficiency in the proximal zone of the root apical meristem. Disruption of HYP1 leads to increased Fe and callose accumulation in the root meristem and causes significant transcriptional changes in roots. We further demonstrate that HYP1 activity overcomes malate-induced Fe accumulation, thereby preventing Fe-dependent root growth arrest in response to low P. Collectively, our results uncover an ascorbate-dependent metalloreductase that is critical to protect root meristems of P-deficient plants from increased Fe availability and provide insights into the physiological function of the yet poorly characterized but ubiquitous CYBDOM proteins.

Abstract Background Automated segmentation of spinal magnetic resonance imaging (MRI) plays a vital role both scientifically and clinically. However, accurately delineating posterior spine structures is challenging. Methods This retrospective study, approved by the ethical committee, involved translating T1-weighted and T2-weighted images into computed tomography (CT) images in a total of 263 pairs of CT/MR series. Landmark-based registration was performed to align image pairs. We compared two-dimensional (2D) paired — Pix2Pix, denoising diffusion implicit models (DDIM) image mode, DDIM noise mode — and unpaired (SynDiff, contrastive unpaired translation) image-to-image translation using “peak signal-to-noise ratio” as quality measure. A publicly available segmentation network segmented the synthesized CT datasets, and Dice similarity coefficients (DSC) were evaluated on in-house test sets and the “MRSpineSeg Challenge” volumes. The 2D findings were extended to three-dimensional (3D) Pix2Pix and DDIM. Results 2D paired methods and SynDiff exhibited similar translation performance and DCS on paired data. DDIM image mode achieved the highest image quality. SynDiff, Pix2Pix, and DDIM image mode demonstrated similar DSC (0.77). For craniocaudal axis rotations, at least two landmarks per vertebra were required for registration. The 3D translation outperformed the 2D approach, resulting in improved DSC (0.80) and anatomically accurate segmentations with higher spatial resolution than that of the original MRI series. Conclusions Two landmarks per vertebra registration enabled paired image-to-image translation from MRI to CT and outperformed all unpaired approaches. The 3D techniques provided anatomically correct segmentations, avoiding underprediction of small structures like the spinous process. Relevance statement This study addresses the unresolved issue of translating spinal MRI to CT, making CT-based tools usable for MRI data. It generates whole spine segmentation, previously unavailable in MRI, a prerequisite for biomechanical modeling and feature extraction for clinical applications. Key points • Unpaired image translation lacks in converting spine MRI to CT effectively. • Paired translation needs registration with two landmarks per vertebra at least. • Paired image-to-image enables segmentation transfer to other domains. • 3D translation enables super resolution from MRI to CT. • 3D translation prevents underprediction of small structures. Graphical Abstract

In past decades, ash dieback has caused a rapid decline of European ash (Fraxinus excelsior) in temperate forests of Europe. Numerous studies focus on mitigating the negative impacts of ash dieback to forest ecosystems or identifying resistant genotypes. The role of natural selection toward genotypes withstanding ash dieback for ash regeneration has been less frequently studied with experimental means to date. This is, however, necessary in times of global change, because the preservation of ash in Europe’s forests will depend, above all, on the adaptability of the future generations of ash trees. To quantify the extent and effects of ash dieback severity for ash regeneration we selected five forest stands moderately damaged and five forest stands highly damaged by ash dieback, in Schleswig-Holstein, Germany. We reciprocally transplanted naturally regenerated ash seedlings sampled in the field between these 10 sites. A shading treatment added to each half of the plots per site was meant to test for effects of altered light conditions in the herb layer due to canopy opening caused by ash dieback. With this approach, we tested seedling survival, performance and fungal infection for an interacting effect of origin and target site in regard to ash dieback severity and environmental factors over 2 years and recorded leaf traits (specific leaf area, leaf dry matter content) in the second year. Reduced light conditions under the shading nets had strong effects, influencing first year performance and infection probability as well as second year survival, growth and leaf trait characteristics. Soil conditions had only a marginal influence on transplanted seedlings. Transplantation direction between moderately and highly damaged sites affected infection marginally during the first year and survival as well as leaf traits significantly during the second year. Most notably, seedlings transplanted from moderately damaged to severely damaged sites exhibited the highest infection probability and lowest SLA, while seedlings transplanted vice versa were least likely to be infected and exhibited the highest SLA. Results hint at a first filtering effect by the ash dieback history of a forest stand and might indicate a transition from ecologically to evolutionary driven differentiation of ash seedling responses.

Review of Wittgenstein’s Philosophy in 1929, edited by Florian Franken Figueiredo.

BackgroundDespite therapy advances, one of the leading causes of cancer deaths still remains lung cancer. To improve current treatments or prevent non-small cell lung cancer (NSCLC), the role of the nutrition in cancer onset and progression needs to be understood in more detail. While in colorectal cancer, the influence of local microbiota derived SCFAs have been well investigated, the influence of SCFA on lung cancer cells via peripheral blood immune system should be investigated more deeply. In this respect, nutrients absorbed via the gut might affect the tumor microenvironment (TME) and thus play an important role in tumor cell growth.ObjectiveThis study focuses on the impact of the short-chain fatty acid (SCFA) Sodium Butyrate (SB), on lung cancer cell survival. We previously described a pro-tumoral role of glucose on A549 lung adenocarcinoma cell line. In this study, we wanted to know if SB would counteract the effect of glucose and thus cultured A549 and H520 in vitro with and without SB in the presence or absence of glucose and investigated how the treatment with SB affects the survival of lung cancer cells and its influence on immune cells fighting against lung cancer.MethodsIn this study, we performed cell culture experiments with A549, H520 and NSCLC-patient-derived epithelial cells under different SB levels. To investigate the influence on the immune system, we performed in vitro culture of peripheral mononuclear blood cells (PBMC) from control, smoker and lung cancer patients with increasing SB concentrations.ResultsTo investigate the effect of SB on lung tumor cells, we first analyzed the effect of 6 different concentrations of SB on A549 cells at 48 and 72 hours cell culture. Here we found that, SB treatment reduced lung cancer cell survival in a concentration dependent manner. We next focused our deeper analysis on the two concentrations, which caused the maximal reduction in cell survival. Here, we observed that SB led to cell cycle arrest and induced early apoptosis in A549 lung cancer cells. The expression of cell cycle regulatory proteins and A549 lung cancer stem cell markers (CD90) was induced. Additionally, this study explored the role of interferon-gamma (IFN-γ) and its receptor (IFN-γ-R1) in combination with SB treatment, revealing that, although IFN-γ-R1 expression was increased, IFN-γ did not affect the efficacy of SB in reducing tumor cell viability. Furthermore, we examined the effects of SB on immune cells, specifically CD8+ T cells and natural killer (NK) cells from healthy individuals, smokers, and NSCLC patients. SB treatment resulted in a decreased production of IFN-γ and granzyme B in CD8+ T cells and NK cells. Moreover, SB induced IFN-γ-R1 in NK cells and CD4+ T cells in the absence of glucose both in PBMCs from controls and NSCLC subjects.ConclusionOverall, this study highlights the potential of SB in inhibiting lung cancer cell growth, triggering apoptosis, inducing cell cycle arrest, and modulating immune responses by activating peripheral blood CD4+ T cells while selectively inducing IFN-γ-R1 in NK cells in peripheral blood and inhibiting peripheral blood CD8+ T cells and NK cells. Thus, understanding the mechanisms of action of SB in the TME and its influence on the immune system provide valuable insights of potentially considering SB as a candidate for adjunctive therapies in NSCLC.

Background/objectiveInsufficiency of respiratory muscles is the most important reason for mortality in the natural history of SMA. Thus, improvement or stabilization of respiratory function by disease-modifying therapies (DMT) is a very important issue.MethodsWe examined respiratory function using forced vital capacity (FVC) in 42 adult SMA patients (2 SMA type 1, 15 SMA type 2, 24 SMA type 3, 1 SMA type 4, median age 37 years, range 17–61 years) treated with nusinersen for a median of 22.1 months (range 2.1 to 46.7 months). Change in FVC was assessed using mixed effects linear regression models.ResultsBaseline FVC differed significantly between SMA type 1 (4.0, 8.0%), 2 (median 22.0%, IQR 18.0–44.0), 3 (median 81.0%, IQR 67.0–90.8) and, respectively, type 4 (84.0%) patients reflecting the heterogeneity of respiratory impairment based on the SMA type in adulthood (p

X-ray Free Electron Lasers (XFELs) allow the collection of high-quality serial femtosecond crystallography data. The next generation of megahertz superconducting FELs promises to drastically reduce data collection times, enabling the capture of more structures with higher signal-to-noise ratios and facilitating more complex experiments. Currently, gas dynamic virtual nozzles (GDVNs) stand as the sole delivery method capable of best utilizing the repetition rate of megahertz sources for crystallography. However, their substantial sample consumption renders their use impractical for many protein targets in serial crystallography experiments. Here, we present a novel application of a droplet-on-demand injection method, which allowed operation at 47 kHz at the European XFEL (EuXFEL) by tailoring a multi-droplet injection scheme for each macro-pulse. We demonstrate a collection rate of 150 000 indexed patterns per hour. We show that the performance and effective data collection rate are comparable to GDVN, with a sample consumption reduction of two orders of magnitude. We present lysozyme crystallographic data using the Large Pixel Detector at the femtosecond x-ray experiment endstation. Significant improvement of the crystallographic statistics was made by correcting for a systematic drift of the photon energy in the EuXFEL macro-pulse train, which was characterized from indexing the individual frames in the pulse train. This is the highest resolution protein structure collected and reported at the EuXFEL at 1.38 Å resolution.

Individuals’ participation in daily routine activities varies according to the situations they live in. Gender roles and marital status drive them to take part in various economic, leisure and travel activities. Married (or cohabiting) individuals, in comparison to singles, juggle activities interdependently with their partners' resources and work allocation, resulting in potentially complex intersecting schedules. The primary aim of this research is to explore the complexity (measured using Shannon’s entropy) of individuals’ activity patterns by considering diverse factors such as demographics, job/education, residential location, travel behaviour, gendered multitasking behaviour, time use preferences and partner interactions. To examine variations in complexity, we developed three separate models for single and partnered respondents, and all respondents, respectively. We used German Time Use Survey 2012/13 data and employed multilevel linear regression models. Gender interaction variables were additionally included in the analysis to examine the gender differences in coefficients. In general, our results suggest that activity pattern complexity is positively associated with demographics (being women, having young children), job/education (high levels of education, working in non-market sector), travel behaviour (number of trips, car, public transport and cycling), time spent on unpaid multitasking, preference for time use (leisure and unpaid work) and additional work hour preferences, whereas full-time/overtime working, paid multitasking negatively affects the complexity. For partnered respondents, factors such as increase in age, increase in income, working in shifts and time spent on paid multitasking have significant negative effects on the complexity of activity patterns, while partners’ time spent on unpaid work and leisure activities positively affects respondents’ complexity. The gender interaction with multitasking behaviour reveals that men’s activity patterns are increasingly complex with more time spent on unpaid multitasking, while for women, the complexity of activity patterns is positively associated with more time spent on paid multitasking.