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Exposure to air pollutants has been associated with adverse health outcomes in adults and children who were prenatally exposed. In addition to reducing exposure to air pollutants, it is important to identify their biologic targets in order to mitigate the health consequences of exposure. One molecular change associated with prenatal exposure to air pollutants is DNA methylation (DNAm), which has been associated with changes in placenta and cord blood tissues at birth. However, little is known about how air pollution exposure impacts the sperm epigenome, which could provide important insights into the mechanism of transmission to offspring. In the present study, we explored whether exposure to particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, nitrogen dioxide (NO2), or ozone (O3) was associated with DNAm in sperm contributed by participants in the Early Autism Risk Longitudinal Investigation prospective pregnancy cohort. Air pollution exposure measurements were calculated as the average exposure for each pollutant measured within 4 weeks prior to the date of sample collection. Using array-based genome-scale methylation analyses, we identified 80, 96, 35, and 67 differentially methylated regions (DMRs) significantly associated with particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, NO2, and O3, respectively. While no DMRs were associated with exposure to all four pollutants, we found that genes overlapping exposure-related DMRs had a shared enrichment for gene ontology biological processes related to neurodevelopment. Together, these data provide compelling support for the hypothesis that paternal exposure to air pollution impacts DNAm in sperm, particularly in regions implicated in neurodevelopment.

Abstract Background Extreme floods are known to severely reorganise inhabited landscapes by inundation, clogging, scouring and damaging infrastructure and lives. However, their post-event impacts are poorly understood, especially concerning coupled hillslope channel feedbacks such as the reactivation of slope instabilities connected to the river and that may be able to block it upon sudden failure. The July 2021 Ahr valley flood exemplified this ability of concurrent and sustained landscape reorganisation. Here, we study a retrogressive slope instability near the town of Müsch, in the upper Ahr valley using field mapping, repeat airborne laser scanning, electrical resistivity tomography and passive seismic monitoring to reveal the failure geometry, its mechanisms and transient activity. Results The old landslide developed in lower Devonian rocks. It is 100 m wide, 200 m long and approximately 15–20 m deep, which leads to a total volume of about 430,000 m3. This landslide was severely undercut by the 2021 flood with 7000 m3 of material eroded at the landslide toe. The landslide has started to react. Given the narrow section of the river at this location, there is a potential landslide dam hazard. We modelled the inundation volumes and back fill times for different failure scenarios, ranging between 20,000 m3 and 330,000 m3 accumulating within 5 min and 20 h. Conclusions Our results imply a need to systematically screen flood impacted landscapes for sustained post-event hillslope activity that governs hillslope-channel coupling, driving both persistent sediment injection into the stream and sudden river blocking and subsequent damming.

Mobility in metropolitan regions is changing. The distribution of space in cities, the design of transport modes, and the organization of mobility are being re-thought. However, no matter the changes and innovations on the way to a more sustainable future, essential constants must be upheld: In the event of minor, regionally limited emergencies, medical assistance must reach those in need quickly. When dealing with large-scale emergencies, the ability to evacuate the area promptly must be ensured. The impact analysis of mobility innovations on emergency services within urban areas so far has been based purely on empirical observations using existing data. Currently, it is only possible to analyze what-if considerations in a limited way. Nevertheless, due to the increasingly rapid changes in mobility, a comprehensive and interlinked analysis will be necessary. This is the key contribution of rescuePY: rescuePY is a simulation suite based on the mesoscopic and microscopic simulation environment hybridPY. It allows holistic and microscopic transport modeling of rescue infrastructure to quantify the impact of the mobility transition towards higher sustainability on the performance of rescue services. The main features of this software are: • Rescue system assessment for strategic, long-term planning • Mobility-influence studies for operative, mid-term planning • Activity-based urban evacuation modeling The capabilities of rescuePY are demonstrated by two applications: a simulation- based, mesoscopic system analysis of emergency services in Munich compared to real-world data and microscopic modeling of emergency vehicles (EMVs) in different road architectures. Ongoing developments aim to improve the evaluation methodology for the aggregated impact analysis of mobility innovations on rescue response services.

Total knee arthroplasty (TKA) is a well-established and successful treatment option for patients with end-stage osteoarthritis of the knee, providing high patient satisfaction. Robotic systems have been widely adopted to perform TKA in orthopaedic centres. The exact spatial positions of the femur and tibia are usually determined through pinned trackers, providing the surgeon with an exact illustration of the axis of the lower limb. The drilling of holes required for mounting the trackers creates weak spots, causing adverse events such as bone fracture. In the presented computational feasibility study, time differential electrical impedance tomography is used to locate the femur positions, thereby the difference in conductivity distribution between two distinct states s0 and s1 of the measured object is reconstructed. The overall approach was tested by simulating five different configurations of thigh shape and considered tissue conductivity distributions. For the cylinder models used for verification and reference, the reconstructed position deviated by about ≈1 mm from the actual bone centre. In case of models mimicking a realistic cross section of the femur position deviated between 7.9 mm 24.8 mm. For all models, the bone axis was off by about φ=1.50° from its actual position.

We present measurements of the angular distribution of re-emitted light from tetraphenyl butadiene thin films when exposed to 128 nm light, which is the peak of the liquid Argon (LAr) scintillation spectrum, in vacuum. Films ranging from 250 nm to 5.5 μm in thickness are measured. All films were fabricated by evaporation deposition on ultraviolet transmitting (UVT) acrylic substrates. Preliminary comparisons of the angular distribution to that produced by a detailed Monte Carlo model are also presented. The current shortcomings of the model are discussed and future plans briefly outlined.

ABSTRACTWe present a detailed geomorphological map (1:5000-scale) of a middle mountainous area in Jena, Germany. To overcome limitations and to extend the possibility of manually digital mapping in a structural way, we propose an approach using geographic information systems (GIS) and high-resolution digital data. The geomorphological map features were extracted by manually interpreting and analyzing the combination of different data sources using light detection and ranging (LiDAR) data. A combination of topographic and geological maps, digital orthophotos (DOPs), Google Earth images, field investigations, and derivatives from digital terrain models (DTMs) revealed that it is possible to generate the geomorphologic features involved in classical mapping approaches. LiDAR-DTM and land surface parameters (LSPs) can provide better results when incorporating the visual interpretation of multidirectional hillshade and LSP composite maps.Findings enabled us to systematically delineate landforms and geomorphological process domains. We suggest that further use of digital data should be undertaken to support analysis and applications.

Mitochondrial function depends crucially on the maintenance of multiple mitochondrial DNA (mtDNA) copies. Surprisingly, the cellular mechanisms regulating mtDNA copy number remain poorly understood. Through a systematic high-throughput approach in Saccharomyces cerevisiae, we determined mtDNA-to-nuclear DNA ratios in 5148 strains lacking nonessential genes. The screen revealed MRX6, a largely uncharacterized gene, whose deletion resulted in a marked increase in mtDNA levels, while maintaining wild type-like mitochondrial structure and cell size. Quantitative superresolution imaging revealed that deletion of MRX6 alters both the size and the spatial distribution of mtDNA nucleoids. We demonstrate that Mrx6 partially colocalizes with mtDNA within mitochondria and interacts with the conserved Lon protease Pim1 in a complex that also includes Mam33 and the Mrx6-related protein Pet20. Acute depletion of Pim1 phenocopied the high mtDNA levels observed in Δmrx6 cells. No further increase in mtDNA copy number was observed upon depletion of Pim1 in Δmrx6 cells, revealing an epistatic relationship between Pim1 and Mrx6. Human and bacterial Lon proteases regulate DNA replication by degrading replication initiation factors, suggesting a model in which Pim1 acts similarly with the Mrx6 complex, providing a scaffold linking it to mtDNA.

Abstract Objective We aimed to investigate whether (1) psychological and social indicators influence survival in patients diagnosed with cancer or haematologic malignancies when important biological aspects are controlled for, (2) psychological, social and biological indicators can be utilised to design one collated index for survival, usable in clinical practice to identify patients at risk of shorter survival and to improve personalised healthcare provision. Methods In this cross‐sectional study, 2263 patients with cancer or haematologic malignancies participated. We analysed 15 biological, psychological and social indicators as risk factors for survival with a Cox proportional hazards model. Indicators significantly associated with survival were combined to compute models for the identification of patient groups with different risks of death. The training sample contained 1122 patients. Validation samples included the remaining 1141 patients, the total sample, as well as groups with different cancer entities. Results Five indicators were found to significantly impact survival: Cancer site (HR: 3.56), metastatic disease (HR: 1.88), symptoms of depression (HR: 1.34), female sex (HR: 0.73) and anaemia (HR: 0.48). Combining these indicators to a model, we developed the Cancer Survival Index, identifying three distinct groups of patients with estimated survival times of 47.2 months, 141 months and 198.2 months (p

Abstract Background Cannabis legalization is expanding and men are the predominant users. We have limited knowledge about how cannabis impacts sperm and whether the effects are heritable. Results Whole genome bisulfite sequencing (WGBS) data were generated for sperm of rats exposed to: (1) cannabis extract (CE) for 28 days, then 56 days of vehicle only (~ one spermatogenic cycle); (2) vehicle for 56 days, then 28 days of CE; or (3) vehicle only. Males were then mated with drug-naïve females to produce F1 offspring from which heart, brain, and sperm tissues underwent analyses. There were 3321 nominally significant differentially methylated CpGs in F0 sperm identified via WGBS with select methylation changes validated via bisulfite pyrosequencing. Significant methylation changes validated in F0 sperm of the exposed males at the gene 2-Phosphoxylose Phosphatase 1 (Pxylp1) were also detectable in their F1 sperm but not in controls. Changes validated in exposed F0 sperm at Metastasis Suppressor 1-Like Protein (Mtss1l) were also present in F1 hippocampal and nucleus accumbens (NAc) of the exposed group compared to controls. For Mtss1l, a significant sex-specific relationship between DNA methylation and gene expression was demonstrated in the F1 NAc. Phenotypically, rats born to CSE-exposed fathers exhibited significant cardiomegaly relative to those born to control fathers. Conclusions This is the first characterization of the effect of cannabis exposure on the entirety of the rat sperm methylome. We identified CE-associated methylation changes across the sperm methylome, some of which persisted despite a “washout” period. Select methylation changes validated via bisulfite pyrosequencing, and genes associated with methylation changes were involved in early developmental processes. Preconception CE exposure is associated with detectable changes in offspring DNA methylation that are functionally related to changes in gene expression and cardiomegaly. These results support that paternal preconception exposure to cannabis can influence offspring outcomes.

IntroductionLocal therapeutic hypothermia (32°C) has been linked experimentally to an otoprotective effect in the electrode insertion trauma. The pathomechanism of the electrode insertion trauma is connected to the activation of apoptosis and necrosis pathways, pro-inflammatory and fibrotic mechanisms. In a whole organ cochlea culture setting the effect of therapeutic hypothermia in an electrode insertion trauma model is evaluated.Material and MethodsThe cochleae of C57Bl6/J mice (Charles River®, Freiburg, Germany) are cultured for 24 hours at 37°C and 32°C after inserting a fishing line through the round window simulating an insertion trauma. The resulting effect was evaluated for the apoptotic reaction – B-cell-Lymphoma-2-Associated-X-Protein (BAX), B-Cell-Lymphoma-2-Protein (BCL2) and Cleaved-Caspase-3 (CC3) –, the inflammatory response – Tumor-Necrosis-Factor-Alpha (TNFα), Interleukin-1-Beta (IL-1Imm) and Cyclooxygenase-2 (COX2) – and proliferation process – Transforming-Growth-Factor-Beta-1 (TGFβ1) – using immunohistochemistry and real-time PCR technique. A minimum of 12 cochlea per experiment were used.ResultsA pro-apoptotic situation was observed in the normothermic group (BAX, CC3 ˃ Bcl2) whereas an anti-apoptotic constellation was found at 32°C culture conditions (BAX, CC3 < Bcl2). Furthermore the effect of the IT knowing to effect the pro-inflammatory cytokine (TNFα, Il1β) and enzyme (COX2) expression has been reproduced. This reaction was reversed with the application of therapeutic hypothermia resulting in significant lower pro-inflammatory cytokine (TNFα, Il1β) and enzyme (COX2) expression. TGFβ1 was increased by hypothermia.DiscussionConcluding a protective effect of hypothermia on the experimental electrode insertion trauma can be described by an anti-apoptotic and anti-inflammatory reaction.

Simple Summary: The optimal selection of patients with advanced high-grade serous ovarian cancer (HGSOC) who are likely to benefit from upfront cytoreductive surgery remains challenging. With the results of the TRUST trial, the fifth randomized phase III trial comparing oncologic outcomes of primary versus interval cytoreductive surgery, expected to be presented soon, there is a high unmet clinical need to define novel biomarkers to optimize pretherapeutic patient assessment and allow for more personalized clinical decision making. Building on the growing evidence of the predictive and prognostic value of fibrinogen in various solid cancers, this study is the first to observe an independent association between the "Fibrinogen–Albumin-Ratio Index" (FARI) and surgical outcomes in patients with advanced HGSOC undergoing primary cytoreductive surgery. Given that the FARI seems to act as a surrogate for intra-abdominal tumor load, the further clinical validation of this cost-effective and readily available biomarker appears promising. Background/Objectives: The present study evaluates predictive implications of the pretherapeutic Fibrinogen–Albumin-Ratio Index (FARI) in high-grade serous ovarian cancer (HGSOC) patients undergoing primary cytoreductive surgery. Methods: This retrospective study included 161 patients with HGSOC International Federation of Gynecology and Obstetrics (FIGO) stage ≥ IIb, who underwent primary cytoreductive surgery followed by platinum-based chemotherapy. Associations between the FARI and complete tumor resection status were described by receiver operating characteristics, and binary logistic regression models were fitted. Results: Higher preoperative FARI values correlated with higher ascites volumes (r = 0.371, p < 0.001), and higher CA125 levels (r = 0.271, p = 0.001). A high FARI cut at its median (≥11.06) was associated with lower rates of complete tumor resection (OR 3.13, 95% CI [1.63–6.05], p = 0.001), and retrained its predictive value in a multivariable model independent of ascites volumes, CA125 levels, FIGO stage, and Charlson Comorbidity Index (CCI). Conclusions: The FARI appears to act as a surrogate for higher intra-abdominal tumor load. After clinical validation, FARI could serve as a readily available serologic biomarker to complement preoperative patient assessment, helping to identify patients who are likely to achieve complete tumor resection during primary cytoreductive surgery. [ABSTRACT FROM AUTHOR]

Children with autism spectrum disorders often exhibit comorbid behavioral problems. These problems have an impact on the severity of the core symptoms, the progression of the disorder as well as on the families' quality of life. We evaluated the effectiveness of the Stepping Stones Triple P group parent training program as a supplementary intervention in the treatment of children with autism spectrum disorder. Therefore, we employed a single group repeated measures design and assessed child variables via parents' and teachers' judgments at four successive time points. The participants were parents of 24 children with autism spectrum disorder aged between 3.6 and 12 years. We found a significant reduction of comorbid behavioral problems in the children, primarily in the parents' judgment at follow-up. Furthermore, a reduction of the autism spectrum disorder core symptoms emerged. The teachers' judgment particularly revealed an improvement in children's social relationships. Effect sizes were large (eta-squared ranging from 0.14 to 0.23). The findings demonstrate the effectiveness of the Stepping Stones Triple P as a supplementary intervention for reducing comorbid behavioral problems in the treatment of children with autism spectrum disorder. Higher parental self-efficacy and parental attributions, including parents' ability to influence child problem behaviors, are discussed as important factors for the effectiveness of Stepping Stones Triple P.