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Abstract Background Elimination of greenhouse gas emissions in industrial biotechnology requires replacement of carbohydrates by alternative carbon substrates, produced from CO2 and waste streams. Ethanol is already industrially produced from agricultural residues and waste gas and is miscible with water, self-sterilizing and energy-dense. The yeast C. jadinii can grow on ethanol and has a history in the production of single-cell protein (SCP) for feed and food applications. To address a knowledge gap in quantitative physiology of C. jadinii during growth on ethanol, this study investigates growth kinetics, growth energetics, nutritional requirements, and biomass composition of C. jadinii strains in batch, chemostat and fed-batch cultures. Results In aerobic, ethanol-limited chemostat cultures, C. jadinii CBS 621 exhibited a maximum biomass yield on ethanol ( $$Y_{X/S}^{\max}$$ Y X / S max ) of 0.83 g biomass (gethanol)−1 and an estimated maintenance requirement for ATP (m ATP) of 2.7 mmolATP (gbiomass)−1 h−1. Even at specific growth rates below 0.05 h−1, a stable protein content of approximately 0.54 gprotein (gbiomass)−1 was observed. At low specific growth rates, up to 17% of the proteome consisted of alcohol dehydrogenase proteins, followed by aldehyde dehydrogenases and acetyl-CoA synthetase. Of 13 C. jadinii strains evaluated, 11 displayed fast growth on ethanol (μ max > 0.4 h−1) in mineral medium without vitamins, and CBS 621 was found to be a thiamine auxotroph. The prototrophic strain C. jadinii CBS 5947 was grown on an inorganic salts medium in fed-batch cultures (10-L scale) fed with pure ethanol. Biomass concentrations in these cultures increased up to 100 gbiomass (kgbroth)−1, with a biomass yield of 0.65 gbiomass (gethanol)−1. Model-based simulation, based on quantitative parameters determined in chemostat cultures, adequately predicted biomass production. A different protein content of chemostat- and fed-batch-grown biomass (54 and 42%, respectively) may reflect the more dynamic conditions in fed-batch cultures. Conclusions Analysis of ethanol-grown batch, chemostat and fed-batch cultures provided a quantitative physiology baseline for fundamental and applied research on C. jadinii. Its high maximum growth rate, high energetic efficiency of ethanol dissimilation, simple nutritional requirements and high protein content, make C. jadinii a highly interesting platform for production of SCP and other products from ethanol.

Abstract Introduction Enteropathy‐associated T‐cell lymphoma (EATL) is a peripheral T‐cell lymphoma (PTCL) with a poor prognosis. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without etoposide consolidated by autologous stem cell transplantation (ASCT) are recommended for fit PTCL patients. The role of etoposide and ASCT in EATL is unclear. Methods This study reports the incidence, treatment, and outcome of EATL patients using the Netherlands Cancer Registry, with nationwide coverage of >95%. Results All patients diagnosed in 1989–2021 (n = 351, 77% treated) were identified (median age 67 years, 56% male, 50% limited stage). Time period analysis assessed trends in primary therapy and overall survival (OS). Treatment included chemotherapy (CT) (34%), surgery (18%), surgery and CT (19%) or CT followed by ASCT (7%). The 5‐year OS for treated patients with limited versus advanced stage was 19% and 9% respectively. The 2‐year OS improved over time (21%–33%, p = 0.06). Surgery only (hazard ratio [HR] 2.16; 95% confidence interval [CI] 1.55–3.01, p

Objective: This study compares early and long-term outcomes following mitral valve (MV) repair and replacement in patients with mitral regurgitation (MR) and reduced left ventricular ejection fraction (LVEF). Methods: Patients with primary or secondary MR and LVEF

Abstract Background Plants utilize a variety of mechanisms to adapt to fluctuations in phosphorus (P) availability. Potatoes, in comparison to other crops, often display reduced phosphorus use efficiency (PUE) due to their underdeveloped root systems; therefore, understanding the mechanisms underlying PUE is critical for improving it. This study aimed to evaluate the morphological and physiological responses of potatoes to different P levels, with a focus on root system alterations and PUE. Two potato cultivars, a table potato (cv. Milva) and a starch potato (cv. Lady Claire), were subjected to varying P levels (0.5, 2, 5, and 30 mg P L-1 supplied as KH2PO4) in a hydroponic system. Additionally, the plants grown under 0.5 and 2 mg P L-1 were treated with plant growth-promoting Bacillus subtilis (B. subtilis), compared to untreated controls, to investigate the effectiveness of B. subtilis in addressing P deficiency. B. subtilis inoculation was performed by adding a bacterial suspension weekly to the hydroponic nutrient solution. Results The findings illustrated Milva’s ability to efficiently allocate P and sugars to its roots under low P levels, thereby enhancing biomass and facilitating increased P uptake and PUE. Conversely, Lady Claire exhibited lower P assimilation efficiency under low P levels but demonstrated improved efficiency under high P availability. The concentration of P in the nutrient solution affected P uptake and several factors believed to be involved in P utilization, such as root morphology, sugar and indole-3-acetic acid concentration in the roots, and acid phosphatase activity. Gene expression analyses underscored the pivotal roles of StPHT1;1 and StPHT2;1 in P translocation to shoots, particularly in Lady Claire. Inoculation with B. subtilis improved P acquisition efficiency by 10% under low phosphorus levels (P0.5 and P2), particularly in Lady Claire, where shoot and root phosphorus contents increased by 13–25% and 4–13%, respectively. Additionally, B. subtilis displayed higher efficacy in mitigating P deficiency in Lady Claire compared to Milva, particularly under low P levels (P0.5 and P2). Conclusion Milva showed greater phosphorus efficiency than Lady Claire under low P conditions, attributed to higher P and sugar levels in roots, enhancing root growth, P uptake, and translocation to shoots, particularly to young leaves. However, Lady Claire demonstrated a notable increase in P uptake and enhanced responsiveness to B. subtilis inoculation, particularly under low P levels (P0.5 and P2). These findings provide valuable insights for optimizing P management strategies to improve PUE in potatoes, especially under low P levels.

Abstract The effects of ultrafine particle (UFP) inhalation on neurodevelopment, especially during critical windows of early life, remain largely unexplored. The specific time windows during which exposure to UFP might be the most detrimental remain poorly understood. Here, we studied early-life exposure to clean ultrafine carbonaceous particles (UFPC) and neurodevelopment and central nervous system function in offspring. Pregnant wild-type C57BL/6J mice were either sham-exposed (HEPA-filtered air) or exposed to clean ultrafine carbonaceous particles at a concentration of 438 ± 72 μg/m³ (mean ± SD) and a count median diameter of 49 ± 2 nm (CMD ± GSD) via whole-body exposure for four hours per day. For prenatal exposure, mice were exposed for two consecutive days in two exposure periods, while the postnatal exposure was conducted for four consecutive days in two exposure periods. The mice were divided into four groups: (i) sham, (ii) only prenatal exposure, (iii) only postnatal exposure, and (iv) both prenatal and postnatal exposure. Neurodevelopmental behaviour was assessed throughout the life of the offspring using a functional observation battery. Early-life UFPC-exposed offspring exhibited altered anxiety-related behaviour in the open field test, with exclusively postnatally exposed offspring (567 ± 120 s) spending significantly more time within the border zone of the arena compared to the sham group (402 ± 73 s), corresponding to an increase of approximately 41% (p

Abstract Background Non-malignant chronic diseases remain a major public health concern. Given the alterations in lipid metabolism and deposition in the lung and its association with fibrotic interstitial lung disease (fILD) and chronic obstructive pulmonary disease (COPD), this study aimed to detect those alterations using computed tomography (CT)-based analysis of pulmonary fat attenuation volume (CTpfav). Methods This observational retrospective single-center study involved 716 chest CT scans from three subcohorts: control (n = 279), COPD (n = 283), and fILD (n = 154). Fully automated quantification of CTpfav based on lung segmentation and HU-thresholding. The pulmonary fat index (PFI) was derived by normalizing CTpfav to the CT lung volume. Statistical analyses were conducted using Kruskal–Wallis with Dunn’s post hoc tests. Results Patients with fILDs demonstrated a significant increase in CTpfav (median 71.0 mL, interquartile range [IQR] 59.7 mL, p

Abstract Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P

Abstract Increasing evidence exists that the gut microbiome influences toxicity as well as outcomes in a variety of cancers. To investigate the role of the gut microbiome in pediatric neuro-oncology, microbiome analysis has been included in multiple prospective pediatric neuro-oncology clinical trials (NCT05009992, NCT04732065, NCT04775485). In these trials, the OMNIgene-GUTtm preservation tubes are used for the collection of the feces. OMNIgene-GUTtm has demonstrated reliability in preserving the composition of the gut microbiome in adults; however, its validation for use in the pediatric population remains limited. Therefore, we compared the quality of the DNA by 16S rRNA gene sequencing after various methods of stabilizing fecal samples in pediatric populations, from the direct freeze method at − 80 °C to preserving samples with OMNIgene-GUTtm at room temperature for various durations. Our results showed that there were no statistically significant differences between the alpha-diversity, and beta-diversity. However, pairwise differential abundance analyses demonstrated that OMNIgene-GUT™ is superior in maintaining microbial community structure compared to storing samples without any preservation method. With the OMNIgene-GUTtm’s stabilization of the fecal samples being superior and its ease-of-use benefits, it proves to be a valid and ideal method of stabilizing fecal samples for current and future pediatric clinical trials.

Abstract We need comprehensive information to manage and protect biodiversity in the face of global environmental challenges, and artificial intelligence is required to generate that information from vast amounts of biodiversity data. Currently, vision‐based monitoring methods are heterogenous; they poorly cover spatial and temporal dimensions, overly depend on humans, and are not reactive enough for adaptive management. To mitigate these issues, we present a portable, modular, affordable and low‐power device with embedded vision for biodiversity monitoring of a wide range of terrestrial taxa. Our camera uses interchangeable lenses to resolve barely visible and remote targets, as well as customisable algorithms for blob detection, region‐of‐interest classification and object detection to automatically identify them. We showcase our system in six use cases from ethology, landscape ecology, agronomy, pollination ecology, conservation biology and phenology disciplines. Using the same devices with different setups, we discovered bats feeding on durian tree flowers, monitored flying bats and their insect prey, identified nocturnal insect pests in paddy fields, detected bees visiting rapeseed crop flowers, triggered real‐time alerts for waterfowl and tracked flower phenology over months. We measured classification accuracies (i.e. F1‐scores) between 55% and 95% in our field surveys and used them to standardise observations over highly resolved time scales. Our cameras are amenable to situations where automated vision‐based monitoring is required off the grid, in natural and agricultural ecosystems, and in particular for quantifying species interactions. Embedded vision devices such as this will help addressing global biodiversity challenges and facilitate a technology‐aided agricultural systems transformation.

ABSTRACT: Nonsense variants can inactivate gene function by causing the synthesis of truncated proteins or by inducing nonsense mediated decay of messenger RNAs. The occurrence of such variants in the genomes of livestock species is modulated by multiple demographic and selective factors. Even though nonsense variants can have causal effects on embryo lethality, abortions, and disease, their genomic distribution and segregation in domestic goats have not been characterized in depth yet. In this work, we have sequenced the genomes of 15 Murciano-Granadina bucks with an average coverage of 32.92× ± 1.45×. Bioinformatic analysis revealed 947 nonsense variants consistently detected with SnpEff and Ensembl-VEP. These variants were especially abundant in the 3′ end of the protein-coding regions. Genes related to olfactory perception, ATPase activity coupled to transmembrane movement of substances, defense to virus, hormonal response, and sensory perception of taste were particularly enriched in nonsense variants. Seventeen nonsense variants expected to have harmful effects on fitness were genotyped in parent-offspring trios. We observed that several nonsense variants predicted to be lethal based on mouse knockout data did not have such effect, a finding that could be explained by the existence of multiple mechanisms counteracting lethality. These findings demonstrate that predicting the effects of putative nonsense variants on fitness is extremely challenging. As a matter of fact, such a goal could only be achieved by generating a high-quality telomere-to-telomere goat reference genome combined with carefully curated annotation and functional testing of promising candidate variants.

Australia is a sink for low pathogenicity avian influenza viruses, with isolated circulation occurring on the continent. We report the incursion of a Eurasian low pathogenicity avian influenza H5 virus into Australia. This report benefits surveillance and diagnostic work because of the risk and current absence of highly pathogenic avian influenza A(H5N1).

CircRNAs are an important class of RNAs with diverse cellular functions in human physiology and disease. A thorough knowledge of circRNAs including their biogenesis and subcellular distribution is important to understand their roles in a wide variety of processes. However, the analysis of circRNAs from total RNA sequencing data remains challenging. Therefore, we developed Calcifer, a versatile workflow for circRNA annotation. Using Calcifer, we analysed APEX-Seq data to compare circRNA occurrence between whole cells, nucleus and subnuclear compartments. We generally find that circRNAs show higher abundance in whole cells compared to nuclear samples, consistent with their accumulation in the cytoplasm. The notable exception is the single-exon circRNA circCANX(9), which is unexpectedly enriched in the nucleus. In addition, we observe that circFIRRE prevails over the linear lncRNA FIRRE in both the cytoplasm and the nucleus. Zooming in on the subnuclear compartments, we show that circRNAs are strongly depleted from nuclear speckles, indicating that excess splicing factors in this compartment counteract back-splicing. Our results thereby provide valuable insights into the subnuclear distribution of circRNAs. Regarding circRNA function, we surprisingly find that the majority of all detected circRNAs possess complete open reading frames with potential for cap-independent translation. Overall, we show that Calcifer is an easy-to-use, versatile and sustainable workflow for the annotation of circRNAs which expands the repertoire of circRNA tools and allows to gain new insights into circRNA distribution and function.

Abstract Aim The objective of this study was to compare the detection rates of [18F]PSMA-1007 and [18F]Fluciclovine in early biochemical recurrence (BCR) of prostate cancer, i.e. with low prostate-specific antigen (PSA) levels (0.2–5.0 µg/L). Methods This was a prospective, single-center (Radboudumc; Nijmegen, The Netherlands), comparative phase II diagnostic imaging study (NCT04239742). The main inclusion criteria were histologically proven adenocarcinoma of the prostate, BCR after radical treatment with two consecutive (rising) PSA values (0.2–5.0 µg/L). Patients underwent both [18F]PSMA-1007 PET/CT and [18F]Fluciclovine PET/CT within two weeks. Both scans were blindly scored by three independent nuclear medicine physicians. Hereafter, a result per scan and region was generated by consensus. The primary outcome was to compare the detection rate on a patient and region level. Secondary objectives were to determine detection rate stratified for PSA value, inter-reader agreement, and SUV measurements. For lesion confirmation a composite reference score was established using follow-up data. Results Data of fifty patients were included, median age of 71 (IQR: 67–74) years and median PSA value of 0.38 (IQR: 0.30–1.55) µg/L. Detection rates were 68% (34/50) for [18F]PSMA-1007 and 42% (21/50) for [18F]Fluciclovine on a patient level (p

Abstract This bicenter retrospective analysis included 162 patients who had undergone prostate biopsy following prebiopsy MRI, excluding those with PCa identified only in the peripheral zone (PZ). DLR T2WI achieved a 69% reduction in scan time relative to TSE T2WI. The intermethod agreement between the two T2WI sets in terms of the Prostate Imaging Reporting and Data System (PI-RADS) classification and extraprostatic extension (EPE) grade was measured using the intraclass correlation coefficient (ICC) and diagnostic performance was assessed with the area under the receiver operating characteristic curve (AUC). Clinically significant PCa (csPCa) was found in 74 (45.7%) patients. Both T2WI methods showed high intermethod agreement for the overall PI-RADS classification (ICC: 0.907–0.949), EPE assessment (ICC: 0.925–0.957) and lesion size measurement (ICC: 0.980–0.996). DLR T2WI and TSE T2WI showed similar AUCs (0.666–0.814 versus 0.684–0.832) for predicting EPE. The AUCs for detecting csPCa with DLR T2WI (0.834–0.935) and TSE T2WI (0.891–0.935) were comparable in 139 patients with TZ lesions with no significant differences (P > 0.05). The findings suggest that DLR T2WI is an efficient alternative for TZ lesion assessment, offering reduced scan times without compromising diagnostic accuracy.

Abstract Adaptive optics (AO) is a powerful method for correcting dynamic aberrations in numerous applications. When applied to the eye, it enables cellular-resolution retinal imaging and enhanced visual performance and stimulation. Most ophthalmic AO systems correct dynamic aberrations up to 1−2 Hz, the commonly-known cutoff frequency for correcting ocular aberrations. However, this frequency may be grossly underestimated for more clinically relevant scenarios where the medical impact of AO will be greatest. Unfortunately, little is known about the aberration dynamics in these scenarios. A major bottleneck has been the lack of sufficiently fast AO systems to measure and correct them. We develop an ultrafast ophthalmic AO system that increases AO bandwidth by ~30× and improves aberration power rejection magnitude by 500×. We demonstrate that this much faster ophthalmic AO is possible without sacrificing other system performances. We find that the discontinuous-exposure AO-control scheme runs 32% slower yet achieves 53% larger AO bandwidth than the commonly used continuous-exposure scheme. Using the ultrafast system, we characterize ocular aberration dynamics in six clinically-relevant scenarios and find their power spectra to be 10−100× larger than normal. We show that ultrafast AO substantially improves aberration correction and retinal imaging performance in these scenarios compared with conventional AO.

Abstract Repair of double-stranded breaks generated by CRISPR/Cas9 is highly dependent on the flanking DNA sequence. To learn about interactions between DNA repair and target sequence, we measure frequencies of over 236,000 distinct Cas9-generated mutational outcomes at over 2800 synthetic target sequences in 18 DNA repair deficient mouse embryonic stem cells lines. We classify the outcomes in an unbiased way, finding a specialised role for Prkdc (DNA-PKcs protein) and Polm in creating 1 bp insertions matching the nucleotide on the protospacer-adjacent motif side of the break, a variable involvement of Nbn and Polq in the creation of different deletion outcomes, and uni-directional deletions dependent on both end-protection and end-resection. Using our dataset, we build predictive models of the mutagenic outcomes of Cas9 scission that outperform the current standards. This work improves our understanding of DNA repair gene function, and provides avenues for more precise modulation of Cas9-generated mutations.

Abstract Eukaryotes must balance the need for gene transcription by RNA polymerase II (Pol II) against the danger of mutations caused by transposable element (TE) proliferation. In plants, these gene expression and TE silencing activities are divided between different RNA polymerases. Specifically, RNA polymerase IV (Pol IV), which evolved from Pol II, transcribes TEs to generate small interfering RNAs (siRNAs) that guide DNA methylation and block TE transcription by Pol II. While the Pol IV complex is recruited to TEs via SNF2-like CLASSY (CLSY) proteins, how Pol IV partners with the CLSYs remains unknown. Here, we identified a conserved CYC-YPMF motif that is specific to Pol IV and is positioned on the complex exterior. Furthermore, we found that this motif is essential for the co-purification of all four CLSYs with Pol IV, but that only one CLSY is present in any given Pol IV complex. These findings support a “one CLSY per Pol IV” model where the CYC-YPMF motif acts as a CLSY-docking site. Indeed, mutations in and around this motif phenocopy pol iv null and clsy quadruple mutants. Together, these findings provide structural and functional insights into a critical protein feature that distinguishes Pol IV from other RNA polymerases, allowing it to promote genome stability by targeting TEs for silencing.

Abstract Hemoglobin (Hb) performs its physiological function within the erythrocyte. Extracellular Hb has prooxidative and proinflammatory properties and is therefore sequestered by haptoglobin and bound by the CD163 receptor on macrophages. In the present study, we demonstrate a novel process of Hb uptake by macrophages independent of haptoglobin and CD163. Unexpectedly, macrophages do not degrade the entire Hb, but instead transfer it to neighboring cells. We have shown that the phenomenon of Hb transfer from macrophages to other cells is mainly mediated by extracellular vesicles. In contrast to the canonical Hb degradation pathway by macrophages, Hb transfer has not been reported before. In addition, we have used the process of Hb transfer in anticancer therapy, where macrophages are loaded with a Hb-anticancer drug conjugate and act as cellular drug carriers. Both mouse and human macrophages loaded with Hb-monomethyl auristatin E (MMAE) effectively killed cancer cells when co-cultured in vitro.

Abstract Background New onsets of chronic urticaria (CU) have been reported after repeated immunizations, mainly with the Moderna mRNA-1273 vaccine (Spikevax). This study aims to evaluate patients with CU after COVID-19 mRNA vaccination. The contribution of SARS-Cov2 infection, atopy and IgE against the vaccine was analyzed. Methods We monitored the features of patients who developed CU after vaccination through two surveys conducted in 2022 and 2023. Fifty individuals with CU underwent blood tests, and their results were compared with individuals without a history of urticaria (N = 135). The presence of anti-vaccine IgE was tested in 185 individuals with basophil activation tests (BAT). We assessed anti-SARS-Cov2 humoral response, and the presence of IgEs against common respiratory allergens (Phadiatop) as a surrogate for atopy. Results Post-vaccination CU occurs after a median interval of 10 days and significantly more after the Spikevax booster, affecting middle-aged individuals (median 41, 66% females). In 2023, CU was still active in 53% of the cases. Inducible forms of CU, primarily dermographism, are reported in 54% (2022) and 61% (2023) of the cases. BAT positivity is not specific to CU, anti-nucleocapsid positivity, or atopy but is significantly associated with higher anti-spike neutralizing activities and younger age. Four CU patients tolerate an additional dose of mRNA vaccine with no disease exacerbation/recurrence. Conclusions The spikevax booster induces anti-vaccine IgE independently of CU, the latter being not directly associated with COVID-19 infection nor atopy. The tolerance to a new booster in 4/4 patients suggests that the Spikevax vaccine indirectly triggers CU in predisposed individuals.

Abstract Background The use of EQ-5D instruments in clinical, policy and economic applications continues to grow internationally. Population norms studies provide baseline values against which demographic and patient groups are compared and inequality is assessed. This study presents updated EQ-5D-5L population norms for 2022–2023, evaluates inequality and compares the results with those of 2012. Methods Demographic and EQ-5D-5L data were obtained from mutually exclusive, representative samples of adults in three studies conducted from July 2022 through May 2023. EQ-5D-5L index values, EQ VAS scores, and ceilings (all dimensions at level 1) were calculated for age-sex groups and stratifiers including education, income, ethnicity, marital status, and employment status. For inequality, the Kakwani index was calculated for the EQ VAS scores and index values, and ordered logit models were used to obtain odds ratios for reporting higher levels of problems on each dimension for demographic groups. The results were compared with those from 2012 which included applying the value set that had been used for the 2022–2023 population norms to the 2012 states. Results Data were obtained form 2,989 respondents. The mean index value was 0.921, EQ VAS was 79.6 and the ceiling was 31.5%. The dimensions with the highest rates of reported problems at any level (2–5) were pain/discomfort (43%) and anxiety/depression (39%). The Kakwani index was 0.113 for EQ VAS and 0.058 for index values, with sex accounting for the largest relative contribution. Mean index values, EQ VAS scores, and ceilings were lower across all demographic groups in 2022–2023 compared to 2012. Conclusions This is the first study to investigate how EQ-5D-5L population norms have changed within a country over time. Significant changes were observed in the EQ-5D-5L measures and the relative frequencies of reported problems on the dimensions. Inequality increased, and there were changes in the levels of reported problems on the dimensions for demographic groups. Such changes suggest that national population norms should be updated periodically to capture changes in health status, perceptions of health, and health inequality.

Abstract Background Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear. Methods To elucidate the metabolic regulations and molecular underpinnings associated with the specific p53R270H and p53R172H mutant variants (the mouse equivalents of human p53R273H and p53R175H, respectively), we employed a comprehensive approach. This included integrating global metabolomic analysis with epigenomic and transcriptomic profiling in mouse pancreatic cancer cells. Additionally, we assessed metabolic parameters such as oxygen consumption rate and conducted analyses of proliferation and cell–cell competition to validate the biological impact of metabolic changes on pancreatic ductal adenocarcinoma (PDAC) phenotype. Our findings were further corroborated through analysis of clinical datasets from human cancer cohorts. Results Our investigation revealed that the p53R270H variant, but not p53R172H, sustains mitochondrial function and energy production while also influencing cellular antioxidant capacity. Conversely, p53R172H, while not affecting mitochondrial metabolism, attenuates the activation of pro-tumorigenic metabolic pathways such as the urea cycle. Thus, the two variants selectively control different metabolic pathways in pancreatic cancer cells. Mechanistically, p53R270H induces alterations in the expression of genes associated with oxidative stress and reduction in mitochondrial respiration. In contrast, p53R172H specifically impacts the expression levels of enzymes involved in the urea metabolism. However, our analysis of cell proliferation and cell competition suggested that the expression of either p53R270H or p53R172H does not influence confer any selective advantage to this cellular model in vitro. Furthermore, assessment of mitochondrial priming indicated that the p53R270H-driven mitochondrial effect does not alter cytochrome c release or the apoptotic propensity of pancreatic cancer cells. Conclusions Our study elucidates the mutant-specific impact of p53R270H and p53R172H on metabolism of PDAC cancer cells, highlighting the need to shift from viewing p53 mutant variants as a homogeneous group of entities to a systematic assessment of each specific p53 mutant protein. Moreover, our finding underscores the importance of further exploring the significance of p53 mutant proteins using models that more accurately reflect tumor ecology.

This survey examines the impact of the Pillar Two income tax legislation as detailed in the 2023 annual reports of 100 large listed European firms. While 71% of companies indicated that the impact of Pillar Two income taxes was not significant, only a third of companies with an IFRS effective tax rate between 15% and 20% expected the impact to be insignificant. Approximately 25% of companies quantified the expected impact, with 90% of these disclosing it as a point estimate or a range of less than 1 percentage point of ETR. However, only 10% disclosed an expected increase in effective tax rate aligning with the OECD’s estimates. Pillar Two income taxes do not appear to have been a significant audit concern in the 2023 financial statements.

Abstract Background Posttraumatic spinal cord tethering and syringomyelia are considered disabling diseases in patients with spinal cord injury. In symptomatic patients, surgical management can achieve promising clinical outcomes. As the raising economic pressure might jeopardize optimal and thus personalized patient care, we aimed to exemplify expenses of surgical treatment in contrast to reimbursement by the Swiss diagnosis related group (DRG) system. Methods This retrospective investigation includes 60 patients who underwent surgery for spinal cord tethering and syringomyelia. The duration of surgeries was used to estimate the costs of care in the operating room (OR) considering established bench marks. Coverage of costs was calculated by comparing Swiss DRG reimbursements with the expenses from the investigated cases. Results The mean duration of surgeries was 251.0 ± 93.5 min while 2.8 ± 1.4 vertebral segments were treated by spinal cord untethering. The mean OR costs (in USD) were $9,401.2±$3,500.2 (range $4,119.5 to $20,223.0). The mean reimbursement and the ratio of OR costs to reimbursement (in USD) were $24,122.5±$7,409.3 (range $17,249.8 to $31,977.1) and 0.41 ± 0.15 (range 0.14 to 0.74) for standard, and $39,106.0±$4,028.6 (range $35,369.1 to $43,376.8) and 0.24 ± 0.08 (range 0.10 to 0.47) for complex cases, respectively. The estimated costs of surgeries were different from reimbursements (p = 0.005). Conclusions Although the cost of surgical management of patients with posttraumatic spinal cord tethering and syringomyelia are principally covered, it remains questionable if total hospital expenses are sufficiently outweighed by the current reimbursement system. This could potentially limit the availability of best medical care and might endanger personalized patient management.

Abstract We present detailed annual land cover maps for the Baltic Sea region, spanning more than two decades (2000–2022). The maps provide information on eighteen land cover (LC) classes, including eight general LC types, eight major crop types and grassland, and two peat bog-related classes. Our maps represent the first homogenized annual dataset for the region and address gaps in current land use and land cover products, such as a lack of detail on crop sequences and peat bog exploitation. To create the maps, we used annual multi-temporal remote sensing data combined with a data encoding structure and deep learning classification. We obtained the training data from publicly available open datasets. The maps were validated using independent field survey data from the Land Use/Cover Area Frame Survey (LUCAS) and expert annotations from high-resolution imagery. The quantitative and qualitative results of the maps provide a reliable data source for monitoring agricultural transformations, peat bog exploitation, and restoration activities in the Baltic Sea region and its surrounding countries.

Abstract In May and June of 2021, marine microbial samples were collected for DNA sequencing in East Sound, WA, USA every 4 hours for 22 days. This high temporal resolution sampling effort captured the last 3 days of a Rhizosolenia sp. bloom, the initiation and complete bloom cycle of Chaetoceros socialis (8 days), and the following bacterial bloom (2 days). Metagenomes were completed on the time series, and the dataset includes 128 size-fractionated microbial samples (0.22–1.2 µm), providing gene abundances for the dominant members of bacteria, archaea, and viruses. This dataset also has time-matched nutrient analyses, flow cytometry data, and physical parameters of the environment at a single point of sampling within a coastal ecosystem that experiences regular bloom events, facilitating a range of modeling efforts that can be leveraged to understand microbial community structure and their influences on the growth, maintenance, and senescence of phytoplankton blooms.

Abstract Background Femoral bone metastases (FBM) or lesions (FBL) can lead to loss of mobility and independence due to skeletal-related events (SRE), e.g. pain, deformity and pathological fractures. Aim of this study was to analyze effects of radiotherapy and surgery, different surgical techniques and complications on disease-specific survival (DSS). Methods Patients who underwent palliative therapy for FBM or FBL between 2014 and 2020 were retrospectively analyzed. Chi-square test was used to detect intergroup differences. Survival was calculated using Kaplan-Meier method, Cox regression and compared using log-rank test. Complications were evaluated using Chi-Square test. Results 145 patients were treated for proximal femoral BM/BL or pathologic fractures (10 bilaterally). Three groups were classified: surgery only (S, n = 53), surgery with adjuvant radiation (S + RT, n = 58), and primary radiation only (RT, n = 44). Most common primary tumors were breast (n = 31), prostate (n = 27), and non-small cell lung cancer (n = 27). 47 patients underwent surgery for an impending, 61 for a manifest pathological fracture. There were no significant differences in DSS between the 3 groups (S = 29.8, S + RT = 32.2, RT = 27.1 months), with the S + RT group having the longest one-year survival. Local complications occurred in 25 of 145 patients after a mean interval of 9.9 months. Conclusion Due to the steadily increasing incidence and survival of patients with FBM/FBL, indication for prevention and treatment of painful and immobilizing SREs should be critically assessed. Surgical treatment should always be performed with maximum stability and, whenever possible, adjuvant RT.

Abstract Quantum interference plays an important role in charge transport through single-molecule junctions, even at room temperature. Of special interest is the measurement of the destructive quantum interference dip itself. Such measurements are especially demanding when performed in a continuous mode of operation. Here, we use mechanical modulation experiments at ambient conditions to reconstruct the destructive quantum interference dip of conductance versus displacement. Simultaneous measurements of the Seebeck coefficient show a sinusoidal response across the dip without sign change. Calculations that include electrode distance and energy alignment variations explain both observations quantitatively, emphasizing the crucial role of thermal fluctuations for measurements under ambient conditions. Our results open the way for establishing a closer link between break-junction experiments and theory in explaining single-molecule transport phenomena, especially when describing sharp features in the transmission.

Abstract This study aimed to analyze polymorphisms in Pfcrt, Pfmdr1, and Pfk13 genes’ markers of resistance to Artemisinin-based combination therapy (ACT), in Plasmodium falciparum isolates from southern Brazzaville, 15 years after the adoption of ACT in the Republic of Congo. A total of 369 microscopy-confirmed malaria-infected individuals were enrolled from March to October 2021 in the community and in health facilities during a cross-sectional study. The K76T mutation in the Pfcrt gene, N86Y and Y184F mutations in the Pfmdr1 gene were investigated using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) while the codons region (1005–1300) of the Pfmdr1gene, and Pfk13 gene were sequenced. The prevalences of K76T, N86Y, Y184F mutations were 26.0%, 6.8%, and 27.7%, respectively. However, no mutations were detected in codons 1034, 1042, and 1246 of the Pfmdr1 gene. None of the mutations previously associated with artemisinin-based resistance were detected in the Pfk13 gene. The results reveal a significant decrease in the prevalence of K76T, N86Y, Y184F mutations, in Plasmodium falciparum isolates following the change of therapeutic policy. As artemisinin resistance is emerging throughout Africa, continued surveillance for early detection of these mutations and relevant partner markers of drug resistance are recommended in the Republic of Congo.

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

RESUMEN La estenosis aórtica grave es la valvulopatía más frecuente y su incidencia aumenta cada año. El implante percutáneo de válvula aórtica (TAVI) es la primera línea de tratamiento con cualquier riesgo quirúrgico. Una complicación frecuente del TAVI es una tasa más alta de implante de marcapasos permanente (IMPP) en comparación con la cirugía. La profundidad óptima de implante es fundamental para reducir la tasa de IMPP sin generar otras complicaciones, como la embolización de la válvula. La técnica clásica de implante, en la cual las 3 cúspides están alineadas en el mismo plano, se ha modificado a una proyección de superposición de cúspides, aislando la cúspide no coronaria y superponiendo la izquierda y la derecha. Esta modificación proporciona una visualización óptima durante el despliegue y facilita obtener la profundidad deseada para reducir la tasa de IMPP. Otra limitación del TAVI es el reacceso coronario debido a la obstrucción de la válvula a los ostium coronarios. La alineación comisural de la prótesis con la válvula nativa facilita la canulación selectiva de las coronarias después del procedimiento. En la presente revisión se comentan las técnicas y la evidencia sobre estas modificaciones de la técnica de liberación e implante, y cómo pueden mejorar el TAVI.

ABSTRACT Severe aortic stenosis is the most frequent valve condition requiring surgery, and its incidence is increasing yearly. Transcatheter aortic valve implantation (TAVI) is the first-line treatment for patients at all levels of surgical risk. Nevertheless, modifications to the procedure often appear to improve clinical outcomes. A major concern after TAVI is the higher rate of permanent pacemaker implantation (PPMI) compared with surgical valve replacement. Optimal implantation depth is crucial to reduce the burden of PPMI without causing serious complications such as valve embolization. The classic implantation technique, where the 3 cusps are aligned in the same plane, has been modified to a cusp overlap projection by isolating the noncoronary cusp and superimposing the left and right cusps. This simple modification provides optimal visualization during deployment and helps to achieve the desired implant depth to reduce conduction disturbances and PPMI. Another limitation after TAVI is coronary reaccess due to the frame of the transcatheter valve obstructing the coronary ostia. Commissural alignment of the prostheses with the native valve may facilitate selective cannulation of the coronary arteries after this procedure. This review will discuss the techniques and supporting evidence for these modifications to the deployment and implant projection methods, and how they can improve TAVI outcomes.

Abstract Background Off-the-shelf stems offer a wide variety of fixation methods for revision arthroplasty and intercalary tumour implants. However, in extensive defects or needed resection with minimal bone stock left, solid fixation is often not feasible with these implants. Custom-made stem solutions (CSS) offer a viable alternative in these cases to achieve joint preservation. Methods Between 2017 and 2024 14 patients (15 implants) were treated in a single-centre study. CSS were indicated if the remaining bone stock was deemed insufficient for normal stem fixation due to tumour resection or previous operations. Postoperative analysis was conducted to evaluate the functional outcome as well as revision rates. Results Implantation was possible in all cases, during the follow-up of 30 (SD 18; 6–66) months revision was needed in five cases; with one aseptic loosening, one screw loosening and three PJI cases. Mean MSTS score was 24 (SD 5; 17–30). Conclusion Custom-made stem solutions show promising results in extreme cases. Especially as a preservation of the joint is possible, this treatment algorithm should be considered on a case-by-case basis.

Abstract Adult ADHD is associated with increased risk for suicide attempts, as indicated by investigations of population- and community-based cohorts. However, there is little data regarding suicide attempts in a clinical setting. To address this, we used a comprehensively phenotyped clinical adult ADHD (aADHD) cohort to assess to which extent comorbidity, psychosocial adversity, personality, and ADHD symptoms contribute to suicidal behavior in ADHD. Furthermore, we investigated a triallelic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR), which has previously been associated with suicidal behavior. Depression, substance use, eating, and posttraumatic stress disorders were independently associated with past suicide attempts, whereas anxiety, somatoform, and obsessive–compulsive spectrum disorders showed no association. Pulmonary diseases also showed an association with suicidal behavior. Psychosocial factors including occupational status, marital status/living situation, externalizing behavior and psychiatric family history were strongly associated with past suicide attempts. ADHD symptoms of inattention and hyperactivity/impulsivity were not associated with past suicide attempts after adjustment for psychiatric comorbidity and psychosocial adversity. However, the personality trait of neuroticism fully mediated the association between depression and suicidal behavior. 5-HTTLPR was not associated with suicidal behavior, but an interaction with ADHD symptoms and subtype was found. Our data suggest that psychiatric comorbidity and psychosocial adversity are key factors for suicidal behavior in aADHD, with neuroticism representing a critical mediator of the association between depression and suicidality. Further research, preferentially with longitudinal study designs is needed to better understand causal factors for suicidal behavior to enable effective preventive action.

Abstract Background This study aims to evaluate the impact of Quebec’s first hospital-at-home-inspired mobile Seniors’ Clinic, the “Clinique des Ainés (CDA)”, on frail older adults’ returns to the Emergency Department (ED), mortality, and hospital Length Of Stay (LOS) and rehospitalizations. Methods Design: Quasi-experimental pre-post implementation cohort study. Population: Patients aged ≥ 75 years admitted to the short-term geriatric unit after an ED consultation (control) or included by the CDA (intervention). Outcomes: return to ED (RtoED), mortality, ED & hospital LOS, and rehospitalizations. Statistical analyses: Multivariable regression modelling. Results Overall, 891 patients were included. At the intervention site (CDA) (n = 437), RtoED were similar at 30 (17.5% & 19.5%, p = 0.58), 90 (34.4% & 37.3%, p = 0.46) and 180 days (47.2% & 54.0%, p = 0.07) in the pre and post-implementation phases. No mortality differences were found. The hospitalization LOS was significantly shorter (28.26 and 14.22 days, p

Abstract Background Rehabilitation plays a crucial role in restoring work ability and facilitating the reintegration of post-COVID patients into the workforce. The impact of rehabilitation on work ability and return to work (RTW) of post-COVID patients remains poorly understood. This study was conducted to assess the work ability and RTW of post-COVID patients before rehabilitation and 12 months after rehabilitation and to identify physical and neuropsychological health factors influencing RTW 12 months after rehabilitation. Methods This longitudinal observational study included 114 post-COVID patients with work-related SARS-CoV-2 infection who underwent inpatient post-COVID rehabilitation with indicative focus on pulmonology and/or psychotraumatology (interval between date of SARS-CoV-2 infection and start of rehabilitation: M = 412.90 days). Employment status, work ability, and the subjective prognosis of employment (SPE) scale were assessed before rehabilitation (T1) and 12 months after rehabilitation (T4). The predictors analysed at T4 were functional exercise capacity, physical activity, subjective physical and mental health status, fatigue, depression, and cognitive function. Longitudinal analyses were performed via the Wilcoxon signed-rank test. Logistic and linear regression analyses identified predictors of work ability and return to work (RTW), whereas mediation analyses examined the relationships between these predictors and work ability. Results At T4, the median of WAI total score indicated poor work ability, which significantly worsened over time (p

Background and objective: Lymphovascular invasion (LVI) is a significant histopathological feature in prostate cancer (PCa) associated with higher risk of biochemical recurrence (BCR) and other adverse outcomes. Our aim was to assess the association of LVI found in radical prostatectomy (RP) specimens with BCR and adverse clinicopathological findings. Methods: A systematic literature search was conducted using the PubMed, Embase, and Web of Science databases in July 2023, with an additional search in May 2024. We included 94 prospective and retrospective studies reporting on LVI in RP specimens and its association with the specified outcomes. Key findings and limitations: Meta-analyses revealed that LVI is significantly associated with higher BCR risk (hazard ratio 1.96, 95% confidence interval [CI] 1.73–2.21), higher pathological tumour stage (odds ratio [OR] 5.77; 95% CI 3.96–8.40), higher Gleason score (OR 5.19, 95% CI 4.12–6.54), lymph node metastasis (OR 11.52, 95% CI 7.65–17.34), distant metastasis (OR 9.10, 95% CI 5.46–15.17), positive surgical margins (OR 2.38, 95% CI 1.83–3.09), extraprostatic extension (OR 5.01, 95% CI 3.11–8.06), seminal vesicle invasion (OR 7.50, 95% CI 3.47–16.23), and perineural invasion (OR 133.71, 95% CI 65.93–271.15). Major limitations of this study include high heterogeneity of the data and the reliance on nonrandomised studies. Conclusions and clinical implications: Our findings reveal that LVI is associated with nearly twofold higher risk of BCR, highlighting its potential role as a critical prognostic marker. Patient summary: We analysed data from multiple studies to understand the impact of the spread of prostate cancer into the lymph or blood vessels, called lymphovascular invasion (LVI). We found that LVI is linked to a higher risk of cancer recurrence after surgery and other negative outcomes. Our findings highlight the importance of considering LVI in treatment decisions for better management of prostate cancer.

Abstract The genomic revolution has fueled rapid progress in synthetic and systems biology, opening up new possibilities for using live biotherapeutic products (LBP) to treat, attenuate or prevent human diseases. Among LBP, bacteria-based therapies are particularly promising due to their ability to colonize diverse human tissues, modulate the immune system and secrete or deliver complex biological products. These bacterial LBP include engineered pathogenic species designed to target specific diseases, and microbiota species that promote microbial balance and immune system homeostasis, either through local administration or the gut-body axes. This review focuses on recent advancements in preclinical and clinical trials of bacteria-based LBP, highlighting both on-site and long-reaching strategies.

Abstract Background Head injuries are the leading cause of trauma in Emergency Departments (EDs). Recent studies have shown epidemiological changes in patients consulting ED for head injuries. The main objective of this study was to describe the profile of head injury patients consulting in the EDs in France and assess i) head injury severity across age groups; ii) the delay between the occurrence of head injury and ED arrival; iii) factors associated with traumatic intracranial hemorrhage (ICH). Methods This cross-sectional study collected patient data over a three-day period in March 2023. All adult patients (≥ 18 years old) admitted to the ED with a head injury (defined as a trauma to the head) were included. TBI severity was classified according to patients’ initial Glasgow Coma Scale score in the ED: severe (3–8); moderate (9 -12); mild (13–15); and simple head trauma in the absence of transient or persistent neurological symptoms. Results Among the 71 participating EDs, 26,008 patients visited EDs and a total of 1070 patients (4.1%, IC 95 3.9—4.4) presented a head injury were included in the study, with a median age of 68.5 [37–85] years old. Most of the patients (66.7%) were referred to ED after a call to the Emergency Medical Dispatcher (EMD). The median time from head injury to ED visit was 2 h [1.0 – 5.5]. Ground-level falls were the leading cause of head injury (60.3%). Most of patient presented a simple head trauma (n = 715, 66.8%) followed by mild TBI (n = 337, 31.5%). CT head scans were performed for 636 patients (59.6%), of which 58 were positive. Traumatic ICH prevalence was 5.4% (95% CI: 4.1–6.9) and three patients (0.3%) required an urgent neurosurgical intervention. Neither preinjury anticoagulant (p = 0.97) nor antiplatelet (p = 0.93) use was associated with an increased risk of traumatic ICH. Conclusions One head injury patient out of two presenting in the ED is aged over 65 years. Patients referred by EMD were more likely to visit ED promptly. The majority of older patients underwent a head CT scan and preinjury anticoagulant use was not associated with increased risk of traumatic ICH.

Abstract Changes in climate and land use are the most often mentioned factors responsible for the current decline in species diversity. To reduce the effect of these factors, we need reliable predictions of future species distributions. This is usually done by utilizing species distribution models (SDMs) based on expected climate. Here we explore the accuracy of such projections: we use orchid (Orchidaceae) recordings and environmental (mainly climatic) data from the years 1901–1950 in SDMs to predict maps of potential species distributions in 1980–2014. This should enable us to compare the predictions of species distributions in 1980–2014, based on records of species distribution in the years 1901–1950, with real data in the 1980–2014 period. We found that the predictions of the SDMs often differ from reality in this experiment. The results clearly indicate that SDM predictions of future species distributions as a reaction to climate change must be treated with caution.

Abstract Mucosal-associated invariant T (MAIT) cells express semi-invariant T cell receptors (TCR) for recognizing bacterial and yeast antigens derived from riboflavin metabolites presented on the non-polymorphic MHC class I-related protein 1 (MR1). Neuroinflammation in multiple sclerosis (MS) is likely initiated by autoreactive T cells and perpetuated by infiltration of additional immune cells, but the precise role of MAIT cells in MS pathogenesis remains unknown. Here, we use experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and find an accumulation of MAIT cells in the inflamed central nervous system (CNS) enriched for MAIT17 (RORγt+) and MAIT1/17 (T-bet+RORγt+) subsets with inflammatory and protective features. Results from transcriptome profiling and Nur77GFP reporter mice show that these CNS MAIT cells are activated via cytokines and TCR. Blocking TCR activation with an anti-MR1 antibody exacerbates EAE, whereas enhancing TCR activation with the cognate antigen, 5-(2-oxopropylideneamino)−6-D-ribitylaminouracil, ameliorates EAE severity, potentially via the induction of amphiregulin (AREG). In summary, our findings suggest that TCR-mediated MAIT cell activation is protective in CNS inflammation, likely involving an induction of AREG.

Abstract Foodborne disease resulting from food sold at urban informal markets is a major public health challenge in Sub-Saharan Africa. This study assessed the impact of an innovative nine-months multi-media campaign engaging a key influencer, aimed at empowering consumers to choose safer ready-to-eat chicken meat at informal street restaurants in Ouagadougou, Burkina Faso. A two-wave panel study assessed associations between recall of TV, radio, billboard, and social media advertisements, and self-reported behavior regarding purchasing and consumption of ready-to-eat chicken at outlets, consumer intentions, knowledge, attitudes, norms, and agency. A panel of randomly selected adult consumers (n = 852) were interviewed pre- and post-campaign, 12 months apart. 60% recalled at least one of the campaign channels when prompted. Mixed-effects models showed associations between prompted recall and feeling better informed about food safety (aOR 1.449) and increased knowledge (0.132 unit increase on total score). Social media recall was associated with higher perceived access to information (aOR 1.449) and knowledge. Billboard recall increased odds of higher perceived health benefits of paying attention to food safety behaviors when purchasing chicken (aOR 2.046). TV ad recall was associated with a 0.159 unit decrease in the gap between consumers’ intentions and behavior. An engaging consumer food safety multimedia campaign that engages key influencers improved food safety awareness and knowledge, ultimately supporting consumers to choose safer chicken at markets.

Abstract Objective Elevated levels of anti‐amyloid‐β (anti‐Aβ) autoantibodies in cerebrospinal fluid (CSF) have been proposed as a diagnostic biomarker for cerebral amyloid angiopathy‐related inflammation (CAA‐RI). We aimed to independently validate the immunoassay for quantifying these antibodies and evaluate its diagnostic value for CAA‐RI. Methods We replicated the immunoassay to detect CSF anti‐Aβ autoantibodies using CSF from CAA‐RI patients and non‐CAA controls with unrelated disorders and further characterized its performance. Moreover, we conducted a literature review of CAA‐RI case reports to investigate neuropathological and CSF evidence of the nature of the inflammatory reaction in CAA‐RI. Results The assay demonstrated a high background signal in CSF, which increased and corresponded with higher total immunoglobulin G (IgG) concentration in CSF (rsp = 0.51, p = 0.02). Assay levels were not elevated in CAA‐RI patients (n = 6) compared to non‐CAA controls (n = 20; p = 0.64). Literature review indicated only occasional presence of B‐lymphocytes and plasma cells (i.e., antibody‐producing cells), alongside the abundant presence of activated microglial cells, T‐cells, and other monocyte lineage cells. CSF analysis did not convincingly indicate intrathecal IgG production. Interpretation We were unable to reproduce the reported elevation of anti‐Aβ autoantibody concentration in CSF of CAA‐RI patients. Our findings instead support nonspecific detection of IgG levels in CSF by the assay. Reviewed CAA‐RI case reports suggested a widespread cerebral inflammatory reaction. In conclusion, our findings do not support anti‐Aβ autoantibodies as a diagnostic biomarker for CAA‐RI.

Abstract Background Non-specific interstitial pneumonia (NSIP) is an interstitial lung disease that can result in end-stage fibrosis. We investigated the influence of body composition and pulmonary fat attenuation volume (CTpfav) on overall survival (OS) in NSIP patients. Methods In this retrospective single-center study, 71 NSIP patients with a median age of 65 years (interquartile range 21.5), 39 females (55%), who had a computed tomography from August 2009 to February 2018, were included, of whom 38 (54%) died during follow-up. Body composition analysis was performed using an open-source nnU-Net-based framework. Features were combined into: Sarcopenia (muscle/bone); Fat (total adipose tissue/bone); Myosteatosis (inter-/intra-muscular adipose tissue/total adipose tissue); Mediastinal (mediastinal adipose tissue/bone); and Pulmonary fat index (CTpfav/lung volume). Kaplan–Meier analysis with a log-rank test and multivariate Cox regression were used for survival analyses. Results Patients with a higher (> median) Sarcopenia and lower (

Abstract High-resolution optical fluorescence microscopies and, in particular, super-resolution fluorescence microscopy, are rapidly adopting highly sensitive cameras as their preferred photodetectors. Camera-based parallel detection facilitates high-speed live cell imaging with the highest spatial resolution. Here, we show that the drive to use ever more sensitive, photon-counting image sensors in cameras can, however, have detrimental effects on the spatial resolution of the resulting images. This is particularly noticeable in applications that demand a high space-bandwidth product, where the image magnification is close to the Nyquist sampling limit of the sensor. Most scientists will often select image sensors based on parameters such as pixel size, quantum efficiency, signal-to-noise performance, dynamic range, and frame rate of the sensor. A parameter that is, however, typically overlooked is the sensor’s modulation transfer function (MTF). We have determined the wavelength-specific MTF of front- and back-illuminated image sensors and evaluated how it affects the spatial resolution that can be achieved in high-resolution fluorescence microscopy modalities. We find significant differences in image sensor performance that cause the resulting spatial resolution to vary by up to 28%. This result shows that the choice of image sensor has a significant impact on the imaging performance of all camera-based optical microscopy modalities.

Abstract DNA double-strand breaks (DSBs) must be properly repaired within diverse chromatin domains to maintain genome stability. Whereas euchromatin has an open structure and is associated with transcription, facultative heterochromatin is essential to silence developmental genes and forms compact nuclear condensates, called polycomb bodies. Whether the specific chromatin properties of facultative heterochromatin require distinct DSB repair mechanisms remains unknown. Here, we integrate single DSB systems in euchromatin and facultative heterochromatin in Drosophila melanogaster and find that heterochromatic DSBs rapidly move outside polycomb bodies. These DSB movements coincide with a break-proximal reduction in the canonical heterochromatin mark histone H3 Lysine 27 trimethylation (H3K27me3). We demonstrate that DSB movement and loss of H3K27me3 at heterochromatic DSBs depend on the histone demethylase dUtx. Moreover, loss of dUtx specifically disrupts completion of homologous recombination at heterochromatic DSBs. We conclude that DSBs in facultative heterochromatin require dUtx-mediated loss of H3K27me3 to promote DSB movement and repair.

Abstract Crossover interference is a phenomenon that affects the number and positioning of crossovers in meiosis and thus affects genetic diversity and chromosome segregation. Yet, the underlying mechanism is not fully understood, partly because quantification is difficult. To overcome this challenge, we introduce the interference length L int that quantifies changes in crossover patterning due to interference. We show that it faithfully captures known aspects of crossover interference and provides superior statistical power over previous measures such as the interference distance and the gamma shape parameter. We apply our analysis to empirical data and unveil a similar behavior of L int across species, which hints at a common mechanism. A recently proposed coarsening model generally captures these aspects, providing a unified view of crossover interference. Consequently, L int facilitates model refinements and general comparisons between alternative models of crossover interference.

Abstract Objectives The control chart is a classic statistical technique in epidemiology for identifying trends, patterns, or alerts. One meaningful use is monitoring and tracking Infant Mortality Rates, which is a priority both domestically and for the World Health Organization, as it reflects the effectiveness of public policies and the progress of nations. This study aims to evaluate the applicability and performance of this technique in Brazilian cities with different population sizes using infant mortality data. Results In this article, we evaluate the effectiveness of the statistical process control chart in the context of Brazilian cities. We present three categories of city groups, divided based on population size and classified according to the quality of the analyses when subjected to the control method: consistent, interpretable, and inconsistent. In cities with a large population, the data in these contexts show a lower noise level and reliable results. However, in intermediate and small-sized cities, the technique becomes limited in detecting deviations from expected behaviors, resulting in reduced reliability of the generated patterns and alerts.

Abstract Hexagonal crystal phase silicon-germanium (hex-SiGe) features efficient direct bandgap emission between 1.5 and 3.4 µm. For expanding its application potential, the key challenge is to demonstrate material gain for enabling a hex-SiGe semiconductor laser. Here we report the transition from the spontaneous emission regime to the stimulated emission-dominated amplified spontaneous emission regime in the optically excited part of a hexagonal Si0.2Ge0.8 nanowire. We observe narrow resonance peaks arising above a spontaneous emission background, which show lasing signatures such as a threshold and a superlinear increase of the emission. A Hakki-Paoli analysis of the height of the cavity resonances provides the gain spectrum of hex-SiGe, showing evidence for a positive material gain. Measurements of the cavity line widths provide an independent assessment of the total cavity loss. While lasing has not been reached, the observation of optical amplification and amplified spontaneous emission provides a clear roadmap toward lasing in hexagonal SiGe. This opens a new pathway for the monolithic integration of a Si-compatible laser within electronic chips.

As multiple UN fora develop parallel rules for sharing benefits from digital sequence information, we urge better coordination. International policymakers should focus on harmonizing new benefit-sharing rules to ensure open access to data, database interoperability, and better benefit sharing outcomes.