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Abstract The inducers of neutrophil extracellular trap (NET) formation are heterogeneous and consequently, there is no specific pathway or signature molecule indispensable for NET formation. But certain events such as histone modification, chromatin decondensation, nuclear envelope breakdown, and NET release are ubiquitous. During NET formation, neutrophils drastically rearrange their cytoplasmic, granular and nuclear content. Yet, the exact mechanism for decoding each step during NET formation still remains elusive. Here, we investigated the mechanism of nuclear envelope breakdown during NET formation. Immunofluorescence microscopic evaluation revealed a gradual disintegration of outer nuclear membrane protein nesprin-1 and alterations in nuclear morphology during NET formation. MALDI-TOF analysis of NETs that had been generated by various inducers detected the accumulation of nesprin-1 fragments. This suggests that nesprin-1 degradation occurs before NET release. In the presence of a calpain-1, inhibitor nesprin-1 degradation was decreased in calcium driven NET formation. Microscopic evaluation confirmed that the disintegration of the lamin B receptor (LBR) and the collapse of the actin cytoskeleton occurs in early and later phases of NET release, respectively. We conclude that the calpain-1 degrades nesprin-1, orchestrates the weakening of the nuclear membrane, contributes to LBR disintegration, and promoting DNA release and finally, NETs formation.

Background: This systematic review has the following aims: (1) to identify measurement tools used globally by healthcare providers to diagnose PCOS in women at elevated risk; (2) to assess the comprehensiveness of these tools regarding mental health and chronic pain; (3) to list strategies for validating, disseminating, and implementing these tools; and (4) to provide future recommendations for experts in healthcare settings. Methods: This review utilized the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and the Arksey and O’Malley York methodology. Studies were sourced from the PubMed, Embase, and Cochrane Library databases, with inclusion criteria focusing on peer-reviewed articles addressing PCOS diagnosis and associated comorbidities. Data extraction and analysis followed the Joanna Briggs Institute (JBI) recommendations. Results: A total of 63 studies met the inclusion criteria. Findings indicate that current screening tools for PCOS often lack comprehensive integration of mental health and chronic pain assessments. Tools like the PCOSQ and its updated version, PCOSQ-50, inadequately address pain-related symptoms, highlighting a gap in holistic patient evaluation. This review identified significant associations between PCOS and mental health disorders, including anxiety and depression, emphasizing the need for mental health screenings as part of PCOS management. Conclusions: There is a critical need for validated PCOS screening tools that encompass both physical and psychological aspects of the condition. Educating healthcare providers on the cultural and social determinants influencing PCOS can improve diagnosis and patient outcomes. Future research should focus on developing holistic screening tools and culturally relevant educational resources, aiming to enhance the overall quality of life for women with PCOS.

Abstract Tuberculosis (TB) remains one of the top 10 causes of death worldwide and still poses a serious challenge to public health. Recent attention to neutrophils has uncovered unexplored areas demanding further investigation. Therefore, the aim of this study was to determine neutrophil activation and circulatory neutrophil extracellular trap (NET) formation in various types of TB. Sera from TB patients (n = 91) and healthy controls (NHD; n = 38) were analyzed for NE-DNA and MPO–DNA complexes, cell-free DNA (cfDNA), and protease activity (elastase). We show that these NET parameters were increased in TB sera. Importantly, NET formation and NE activity were elevated in TB patients with extensive tissue damage when compared to those with minor damage and in patients with relapse, compared to new cases. We discuss the importance of balancing NET formation to prevent tissue damage or even relapse and argue to analyze circulating NET parameters to monitor the risk of disease relapse. To investigate the tissues for NETs and to find the source of the circulating NET degradation products, we collected sections of granulomas in lung and lymph node biopsies. Samples from other diseases with granulomas, including sarcoidosis (SARC) and apical periodontitis (AP), served as controls. Whereas NET formation characterizes the caseating granulomas, both caseating and non-caseating granulomas harbor DNA with unusual conformation. As TB is associated with hypercoagulation and thromboembolism, we further imaged the pulmonary vessels of TB patients and detected vascular occlusions with neutrophil aggregates. This highlights the dual role of neutrophils in the pathology of TB.

Abstract Background and purpose Rare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at unusually low dose levels and are thus difficult to understand considering dose metrics only. When transitioning from double scattering to pencil beam scanning, little consideration was given to increased dose rates observed with the latter delivery paradigm. We explored if dose rate related metrics could provide additional predicting factors for the development of late visual toxicities. Materials and methods Radiation-induced intracranial visual pathway lesions were delineated on MRI for all index cases. Voxel-wise maximum dose rate (MDR) was calculated for 2 patients with observed optic nerve toxicities (CTCAE grade 3 and 4), and 6 similar control cases. Additionally, linear energy transfer (LET) related dose enhancing metrics were investigated. Results For the index cases, which developed toxicities at low dose levels (mean, 50 GyRBE), some dose was delivered at higher instantaneous dose rates. While optic structures of non-toxicity cases were exposed to dose rates of up to 1 to 3.2 GyRBE/s, the pre-chiasmatic optic nerves of the 2 toxicity cases were exposed to dose rates above 3.7 GyRBE/s. LET-related metrics were not substantially different between the index and non-toxicity cases. Conclusions Our observations reveal large variations in instantaneous dose rates experienced by different volumes within our patient cohort, even when considering the same indications and beam arrangement. High dose rate regions are spatially overlapping with the radiation induced toxicity areas in the follow up images. At this point, it is not feasible to establish causality between exposure to high dose rates and the development of late optic apparatus toxicities due to the low incidence of injury.

Social, emotional, and behavioral (SEB) skills comprise a broad set of abilities that are essential for building and maintaining relationships, regulating emotions, selecting and pursuing goals, or exploring novel stimuli. Toward an improved SEB skill assessment, Soto and colleagues recently introduced the Behavioral, Emotional, and Social Skills Inventory (BESSI). Measuring 32 facets from 5 domains with 192 items (assessment duration: [approximately]15 min), BESSI constitutes the most extensive SEB inventory to date. However, so far, BESSI exists only in English. In three studies, we comprehensively validated a novel German-language adaptation, BESSI-G. Moreover, we expanded evidence on BESSI in three ways by (1) assessing the psychometric properties of the 32 individual skill facets, in addition to their domain-level structure; (2) providing first insights into the temporal stabilities of the 32 facets over 1.5 and 8 months; and (3) investigating the domains' and facets' associations with intelligence, in addition to personality traits. Results show that BESSI-G exhibits good psychometric properties (unidimensionality, reliability, factorial validity). Its domain-level structure is highly similar to that of the English-language source version. The facets show high temporal stabilities, convergent validity with personality traits, and discriminant validity with fluid and crystallized intelligence. We discuss implications for research on SEB skills.

OBJECTIVES Virtual reality (VR) appears to be a promising educational tool for otorhinolaryngology (ORL) residency training, as it allows for safe and effective practice immediate feedback and potential improvements in patient outcomes. Despite these advantages, VR has not yet been incorporated into residency training in ORL, which may be due to limited availability or validation and skepticism toward incorporation of new training methods. This study investigates whether a VR model of the temporal bone improves learning success for ORL residents in comparison to standard plastic models and whether it depends on surgeon's experience. We also included a subjective evaluation of the learning experience with both models. METHODS ORL residents and specialists at 2 German university hospitals were tested on their knowledge of temporal bone anatomy after training with either VR or standard plastic models. In addition, we compared knowledge of the temporal bone anatomy before- and after-VR training. Lastly, a subjective survey on the benefits and limitations of VR was conducted to assess participants’ views on this new technology. RESULTS About 85% of the participants considered VR to be better than conventional models and agreed that VR was a useful tool for teaching complex anatomy. Objective evaluation showed significant improvement in knowledge after using VR (before/after comparison), especially in participants with a higher level of preexisting knowledge. Direct comparison to conventional plastic models showed no superiority of the VR model. CONCLUSION VR models in ORL are not only appealing and motivating for residents, but also objectively improve their anatomical knowledge, especially in advanced residency. In addition, VR—in contrast to the plastic model—offers opportunities for further development and optimization.

Postoperative infections are the most common complications faced by surgeons after implant surgery. To address this issue, an emerging and promising approach is to develop antimicrobial coatings using antibiotic substitutes. We investigated the use of polycationic homopolypeptides in a layer-by-layer coating combined with hyaluronic acid (HA) to produce an effective antimicrobial shield. The three peptide-based polycations used to make the coatings, poly(l-arginine) (PAR), poly(l-lysine), and poly(l-ornithine), provided an efficient antibacterial barrier by a contact-killing mechanism against Gram-positive, Gram-negative, and antibiotic-resistant bacteria. Moreover, this activity was higher for homopolypeptides containing 30 amino-acid residues per polycation chain, emphasizing the impact of the polycation chain length and its mobility in the coatings to deploy its contact-killing antimicrobial properties. However, the PAR-containing coating emerged as the best candidate among the three selected polycations, as it promoted cell adhesion and epithelial monolayer formation. It also stimulated nitric oxide production in endothelial cells, thereby facilitating angiogenesis and subsequent tissue regeneration. More interestingly, bacteria did not develop a resistance to PAR and (PAR/HA) also inhibited the proliferation of eukaryotic pathogens, such as yeasts. Furthermore, in vivo investigations on a (PAR/HA)-coated hernia mesh implanted on a rabbit model confirmed that the coating had antibacterial properties without causing chronic inflammation. These impressive synergistic activities highlight the strong potential of PAR/HA coatings as a key tool in combating bacteria, including those resistant to conventional antibiotics and associated to medical devices.

In der antiken Welt war die dynastische oder eponyme Jahreszählung die Regel. Eine Ausnahme von dieser Regel bildete die Seleukidenzeit, über die Paul Kosmin faszinierende Einblicke gewährt hat. Seit Antiochus II. wurde die Seleukidenzeit als Instrument der seleukidischen Macht genutzt, um die seleukidische Herrschaft im gesamten Reich durch Inschriften, Gewichtsmaße, Münzen, Siegel, um nur einige Medien zu nennen, zu visualisieren. Auf den ersten Blick ist es keine Überraschung, die Seleukidenzeit in epigraphischen Zeugnissen in der südlichen Levante sowie in literarischen Dokumenten wie dem ersten Buch der Makkabäer zu finden. Der Status der Ära als Instrument der seleukidischen Macht macht es jedoch schwierig zu verstehen, warum der Autor des ersten Makkabäerbuches an dieser als chronologischem Anker festhielt, obwohl die Intention des Buches gegen das Seleukidenreich gerichtet ist. In 1Makk 13,41-42 datiert er sogar die Einführung Simons in das Hohepriesteramt 143/42 v. Chr. in Judäa nach der Seleukidenzeit und verweist zugleich darauf, dass nun wieder eponym nach Simon datiert wurde. Der Artikel geht auf diese beiden Probleme ein. Erstens wird argumentiert, dass die Abhängigkeit des Autors von 1Makk von der Seleukidenzeit auf ein Abfassungsdatum des Buches hinweist, als Judäa noch unter seleukidischer Herrschaft stand. Zweitens wird die merkwürdig anmutende Einführung der Datierung nach Simon untersucht und in die Formen seleukidischer Herrschaft eingeordnet. In diesem Sinne bedeutete die Gewährung einer eigenen Datierungsformel durch Demetrios II. für Simon eine signifikante politische Aufwertung für ihn, was als Zeichen dafür gewertet werden kann, dass Simon zu einem der wichtigsten Vertreter der Seleukiden wurde.

AimsNeutrophils and neutrophil extracellular traps (NETs) play multifaceted roles in inflammatory diseases. If the balance of NET formation and clearance is disturbed, they contribute to the development and pathogenesis of a plethora of inflammatory diseases. They promote inflammation and tissue degradation, and occlude vessels and ducts. This study focused on the presence of NET remnants generated during the clearance by nucleases and phagocytes.MethodsNET associated parameters in serum and plasma samples from various pathological conditions were investigated. We performed fluorescence-based assays to analyze the concentration of cell free DNA and the activity of neutrophil elastase. The presence of citrullinated histone H3, as well as neutrophil elastase- or myeloperoxidase-DNA complexes were examined employing enzyme-linked immunosorbent assays.ResultsWe analyzed samples from a variety of inflammatory conditions: (I) the rheumatic autoimmune diseases systemic lupus erythematosus, rheumatoid arthritis, and primary Sjögren’s syndrome (II) the inflammatory bowel diseases ulcerative colitis and Crohn’s disease (III) hidradenitits suppurativa and (IV) the viral-induced pathologies Coronavirus disease 2019 (COVID-19), and Post COVID Syndrome (PCS). While most NET associated parameters were detected in all inflammatory conditions, certain markers displayed disease-specific patterns. We compared the markers in terms of the concentration, correlations with each other and to disease activity, and their impact on sample variability. Systemic lupus erythematosus and rheumatoid arthritis were associated with increased levels of cell free DNA, and citrullinated histone H3 as well as neutrophil elastase-activity, respectively. Samples from patients with COVID-19 were characterized by elevated levels of neutrophil elastase- and myeloperoxidase-DNA complexes.ConclusionDifferent diseases are linked to characteristic patterns of NET associated parameters. These patterns offer insights into aberrant NET formation and clearance in different pathologies and may represent key targets for treatment development.

Abstract Complex disease phenotypes often span multiple molecular processes. Functional characterization of these processes can shed light on disease mechanisms and drug effects. Thermal Proteome Profiling (TPP) is a mass-spectrometry (MS) based technique assessing changes in thermal protein stability that can serve as proxies of functional protein changes. These unique insights of TPP can complement those obtained by other omics technologies. Here, we show how TPP can be integrated with phosphoproteomics and transcriptomics in a network-based approach using COSMOS, a multi-omics integration framework, to provide an integrated view of transcription factors, kinases and proteins with altered thermal stability. This allowed us to recover consequences of Poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer cells on cell cycle and DNA damage response as well as interferon and hippo signaling. We found that TPP offers a complementary perspective to other omics data modalities, and that its integration allowed us to obtain a more complete molecular overview of PARP inhibition. We anticipate that this strategy can be used to integrate functional proteomics with other omics to study molecular processes.

Adsorption and desorption of gases on liquid or solid substrates are involved in multiphase processes and heterogeneous chemical reactions. The desorption energy (Edes0), which depends on the intermolecular forces between adsorbate and substrate, determines the residence time of chemical species at interfaces. We show how Edes0 and temperature influence the net uptake or release of gas species, the rates of surface–bulk exchange and surface or bulk reactions, and the equilibration timescales of gas–particle partitioning. Using literature data, we derive a parameterization to estimate Edes0 for a wide range of chemical species based on the molecular mass, polarizability, and oxygen-to-carbon ratio of the desorbing species independent of substrate-specific properties, which is possible because of the dominant role of the desorbing species' properties. Correlations between Edes0 and the enthalpies of vaporization and solvation are rooted in molecular interactions. The relation between Edes0 and desorption kinetics reflects the key role of interfacial exchange in multiphase processes. For small molecules and semi-volatile organics (VOC, IVOC, SVOC), Edes0 values around 10–100 kJ mol−1 correspond to desorption lifetimes around nanoseconds to days at room temperature. Even higher values up to years are obtained at low temperatures and for low volatile organic compounds (LVOC, ELVOC/ULVOC) relevant for secondary organic aerosols (SOA). Implications are discussed for SOA formation, gas–particle partitioning, organic phase changes, and indoor surface chemistry. We expect these insights to advance the mechanistic and kinetic understanding of multiphase processes in atmospheric and environmental physical chemistry, aerosol science, materials science, and chemical engineering.