bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA repair-dependent immunogenic liabilities in colorectal cancer: opportunities from errors
Authors: Amodio V. , Vitiello P. P. , Bardelli A. , Germano G. 
Published: September 2024

AbstractColorectal cancer (CRC) remains one of the major causes of cancer death worldwide. Chemotherapy continues to serve as the primary treatment modality, while immunotherapy is largely ineffective for the majority of CRC patients. Seminal discoveries have emphasized that modifying DNA damage response (DDR) mechanisms confers both cell-autonomous and immune-related vulnerabilities across various cancers. In CRC, approximately 15% of tumours exhibit alterations in the mismatch repair (MMR) machinery, resulting in a high number of neoantigens and the activation of the type I interferon response. These factors, in conjunction with immune checkpoint blockades, collectively stimulate anticancer immunity. Furthermore, although less frequently, somatic alterations in the homologous recombination (HR) pathway are observed in CRC; these defects lead to genome instability and telomere alterations, supporting the use of poly (ADP-ribose) polymerase (PARP) inhibitors in HR-deficient CRC patients. Additionally, other DDR inhibitors, such as Ataxia Telangiectasia and Rad3-related protein (ATR) inhibitors, have shown some efficacy both in preclinical models and in the clinical setting, irrespective of MMR proficiency. The aim of this review is to elucidate how preexisting or induced vulnerabilities in DNA repair pathways represent an opportunity to increase tumour sensitivity to immune-based therapies in CRC.
Unbiased screening identifies regulators of cell-cell adhesion and treatment options in pemphigus
Authors: Franz Henriette , Rathod Maitreyi , Zimmermann Aude , Stüdle Chiara , Beyersdorfer Vivien , Leal-Fischer Karen , Hanns Pauline , Cunha Tomás , Didona Dario , Hertl Michael , Scheibe Marion , Butter Falk , Schmidt Enno , Spindler Volker 
Published: September 2024

AbstractCell-cell junctions, and specifically desmosomes, are crucial for robust intercellular adhesion. Desmosomal function is compromised in the autoimmune blistering skin disease pemphigus vulgaris. We combine whole-genome knockout screening and a promotor screen of the desmosomal gene desmoglein 3 in human keratinocytes to identify novel regulators of intercellular adhesion. Kruppel-like-factor 5 (KLF5) directly binds to the desmoglein 3 regulatory region and promotes adhesion. Reduced levels of KLF5 in patient tissue indicate a role in pemphigus vulgaris. Autoantibody fractions from patients impair intercellular adhesion and reduce KLF5 levels in in vitro and in vivo disease models. These effects were dependent on increased activity of histone deacetylase 3, leading to transcriptional repression of KLF5. Inhibiting histone deacetylase 3 increases KLF5 levels and protects against the deleterious effects of autoantibodies in murine and human pemphigus vulgaris models. Together, KLF5 and histone deacetylase 3 are regulators of desmoglein 3 gene expression and intercellular adhesion and represent potential therapeutic targets in pemphigus vulgaris.
Emerging multiscale insights on microbial carbon use efficiency in the land carbon cycle
Authors: He Xianjin , Abs Elsa , Allison Steven D. , Tao Feng , Huang Yuanyuan , Manzoni Stefano , Abramoff Rose , Bruni Elisa , Bowring Simon P. K. , Chakrawal Arjun , Ciais Philippe , Elsgaard Lars , Friedlingstein Pierre , Georgiou Katerina , Hugelius Gustaf , Holm Lasse Busk , Li Wei , Luo Yiqi , Marmasse Gaëlle , Nunan Naoise , Qiu Chunjing , Sitch Stephen , Wang Ying-Ping , Goll Daniel S. 
Published: September 2024

AbstractMicrobial carbon use efficiency (CUE) affects the fate and storage of carbon in terrestrial ecosystems, but its global importance remains uncertain. Accurately modeling and predicting CUE on a global scale is challenging due to inconsistencies in measurement techniques and the complex interactions of climatic, edaphic, and biological factors across scales. The link between microbial CUE and soil organic carbon relies on the stabilization of microbial necromass within soil aggregates or its association with minerals, necessitating an integration of microbial and stabilization processes in modeling approaches. In this perspective, we propose a comprehensive framework that integrates diverse data sources, ranging from genomic information to traditional soil carbon assessments, to refine carbon cycle models by incorporating variations in CUE, thereby enhancing our understanding of the microbial contribution to carbon cycling.
Mapping domains of early life determinants of future multimorbidity across three UK longitudinal cohort studies
Authors: Stannard S. , Berrington A. , Fraser S. D.S , Paranjothy S. , Hoyle R. B. , Owen R. K. , Akbari A. , Shiranirad M. , Chiovoloni R. , Alwan N. A. 
Published: September 2024

AbstractMany studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We explored how potential multiple early life determinants of multimorbidity can be characterised across three UK cohort studies. We used the National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identified early life variables that fit into 12 conceptualised domains of early life determinants of multimorbidity. Variables were assigned into 12 domains; principal component analysis reduced the dimensionality of the data and structured variables into subgroups. The data audit identified 7 domains in ACONF, 10 domains in NCDS and 12 domains in BCS70. Dominant components included maternal fertility histories within the prenatal, antenatal and birth domain, long-term illnesses within the child health domain, educational ability within the child education and health literacy domain, ethnicity within the demography domain, parental health behaviours within the transgenerational domain, housing within the socioeconomic domain and parental-child interactions within the parental-family domain. We demonstrated that if multiple large scale longitudinal studies are used, there is enough data available for researchers to consider conceptualising early life risk factors of multimorbidity across groups or domains. Such conceptualisation can help challenge the existing understanding of disease aetiology and develop new ideas for prevention of multimorbidity.
Rapid analysis of amatoxins in human urine by means of affinity column chromatography and liquid chromatography-high-resolution tandem mass spectrometry
Authors: Vollmer Aline C. , Fecher-Trost Claudia , Bever Candace S. , Tam Christina C. , Wagmann Lea , Meyer Markus R. 
Published: September 2024

AbstractAnalysis of amatoxins is of great importance as these cyclic peptides contribute to a high number of fatalities each year. Development of analytical approaches needs to focus on rapid, sensitive, and reliable methods. By establishing an affinity column chromatography-based assay using the monoclonal amanitin antibody AMA9G3 and liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS) for the trace detection of α-, β-, and γ-amanitin in human urine samples to confirm ingestion, we report the first approach that extents the current status of amatoxin analysis. The presented procedure allows detection of amatoxins in human urine down to 1 ng/mL. The method was successfully validated qualitatively for α- and γ-amanitin according to international recommendations. A proof of concept was performed by analyzing 37 urine samples after suspected amatoxin consumption submitted for regular clinical toxicological analysis. Using this antibody-based enrichment strategy, acute amatoxin intoxications can be determined within 90 min and due to the high sensitivity and selectivity, a comparable approach using target specific antibodies may also be used for other toxicological relevant peptides.
Comparative analysis of the genomes and aflatoxin production patterns of three species within the Aspergillus section Flavi reveals an undescribed chemotype and habitat-specific genetic traits
Authors: Schamann Alexandra , Soukup Sebastian T. , Geisen Rolf , Kulling Sabine , Schmidt-Heydt Markus 
Published: September 2024

AbstractAflatoxins are the most dangerous mycotoxins for food safety. They are mainly produced by Aspergillus flavus, A. parasiticus, and A. minisclerotigenes. The latter, an understudied species, was the main culprit for outbreaks of fatal aflatoxicosis in Kenya in the past. To determine specific genetic characteristics of these Aspergillus species, their genomes are comparatively analyzed. Differences reflecting the typical habitat are reported, such as an increased number of carbohydrate-active enzymes, including enzymes for lignin degradation, in the genomes of A. minisclerotigenes and A. parasiticus. Further, variations within the aflatoxin gene clusters are described, which are related to different chemotypes of aflatoxin biosynthesis. These include a substitution within the aflL gene of the A. parasiticus isolate, which leads to the translation of a stop codon, thereby switching off the production of the group 1 aflatoxins B1 and G1. In addition, we demonstrate that the inability of the A. minisclerotigenes isolates to produce group G aflatoxins is associated with a 2.2 kb deletion within the aflF and aflU genes. These findings reveal a relatively high genetic homology among the three Aspergillus species investigated. However, they also demonstrate consequential genetic differences that have an important impact on risk-assessment and food safety.
Requirement of Nek2a and cyclin A2 for Wapl-dependent removal of cohesin from prophase chromatin
Authors: Hellmuth Susanne , Stemmann Olaf 
Published: September 2024

AbstractSister chromatid cohesion is mediated by the cohesin complex. In mitotic prophase cohesin is removed from chromosome arms in a Wapl- and phosphorylation-dependent manner. Sgo1-PP2A protects pericentromeric cohesion by dephosphorylation of cohesin and its associated Wapl antagonist sororin. However, Sgo1-PP2A relocates to inner kinetochores well before sister chromatids are separated by separase, leaving pericentromeric regions unprotected. Why deprotected cohesin is not removed by Wapl remains enigmatic. By reconstituting Wapl-dependent cohesin removal from chromatin in vitro, we discovered a requirement for Nek2a and Cdk1/2-cyclin A2. These kinases phosphorylate cohesin-bound Pds5b, thereby converting it from a sororin- to a Wapl-interactor. Replacement of endogenous Pds5b by a phosphorylation mimetic variant causes premature sister chromatid separation (PCS). Conversely, phosphorylation-resistant Pds5b impairs chromosome arm separation in prometaphase-arrested cells and suppresses PCS in the absence of Sgo1. Early mitotic degradation of Nek2a and cyclin A2 may therefore explain why only separase, but not Wapl, can trigger anaphase.
mTOR signalling controls the formation of smooth muscle cell-derived luminal myofibroblasts during vasculitis
Authors: Stock Angus T , Parsons Sarah , Hansen Jacinta A , D’Silva Damian B , Starkey Graham , Fayed Aly , Lim Xin Yi , D’Costa Rohit , Gordon Claire L , Wicks Ian P 
Published: September 2024

AbstractThe accumulation of myofibroblasts within the intimal layer of inflamed blood vessels is a potentially catastrophic complication of vasculitis, which can lead to arterial stenosis and ischaemia. In this study, we have investigated how these luminal myofibroblasts develop during Kawasaki disease (KD), a paediatric vasculitis typically involving the coronary arteries. By performing lineage tracing studies in a murine model of KD, we reveal that luminal myofibroblasts develop independently of adventitial fibroblasts and endothelial cells, and instead derive from smooth muscle cells (SMCs). Notably, the emergence of SMC-derived luminal myofibroblasts—in both mice and patients with KD, Takayasu’s arteritis and Giant Cell arteritis—coincided with activation of the mechanistic target of rapamycin (mTOR) signalling pathway. Moreover, SMC-specific deletion of mTOR signalling, or pharmacological inhibition, abrogated the emergence of luminal myofibroblasts. Thus, mTOR is an intrinsic and essential regulator of luminal myofibroblast formation that is activated in vasculitis patients and therapeutically tractable. These findings provide molecular insight into the pathogenesis of coronary artery stenosis and identify mTOR as a therapeutic target in vasculitis.
Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice
Authors: Hu Guoli , Yu Yilin , Ren Yinshi , Tower Robert J , Zhang Guo-Fang , Karner Courtney M 
Published: September 2024

AbstractOsteoclasts are bone resorbing cells that are essential to maintain skeletal integrity and function. While many of the growth factors and molecular signals that govern osteoclastogenesis are well studied, how the metabolome changes during osteoclastogenesis is unknown. Using a multifaceted approach, we identified a metabolomic signature of osteoclast differentiation consisting of increased amino acid and nucleotide metabolism. Maintenance of the osteoclast metabolic signature is governed by elevated glutaminolysis. Mechanistically, glutaminolysis provides amino acids and nucleotides which are essential for osteoclast differentiation and bone resorption in vitro. Genetic experiments in mice found that glutaminolysis is essential for osteoclastogenesis and bone resorption in vivo. Highlighting the therapeutic implications of these findings, inhibiting glutaminolysis using CB-839 prevented ovariectomy induced bone loss in mice. Collectively, our data provide strong genetic and pharmacological evidence that glutaminolysis is essential to regulate osteoclast metabolism, promote osteoclastogenesis and modulate bone resorption in mice.
A novel family of asymmetric generalized passive voltage‐controlled memristive system
Authors: Cao Hongbo , Liu Jun , Wang Faqiang 
Published: September 2024

AbstractResearch on the physical memristive system is vital for realizing widespread applications of the memristor in practical engineering. In this article, a family of the asymmetric generalized passive voltage‐controlled memristive system (AGPVCMS) is proposed; also the mathematical model of the AGPVCMS is established and its remarkable memristive characteristics are analysed. Especially, the AGPVCMS only consists of the diode bridge and LR filter, however it can enhance its asymmetry as well as display various asymmetrical pinched hysteresis loops in the voltage–current plane, via expediently changing the number of the diodes on different bridge arms. In addition, the effectiveness of the AGPVCMS is verified by the consistency between theoretical and experimental results.
Future challenges in the surgical treatment of breast cancer – Oncoplastic, prophylactic procedures and reconstructive surgery
Authors: Hahn Markus , Böer Bettina , Gürgan Selin , Marx Mario 
Published: September 2024

AbstractMedical knowledge is doubling faster and faster. Surgeons are highly specialized and must be trained not only in surgery, but also in imaging and oncology to meet the modern requirements of a breast center. This article describes what has changed in the surgical treatment of breast cancer over the past 20 years since the introduction of certified breast centers in Germany, and what could change in the future. Pre- and post-operative conferences have become a central component of the interdisciplinary exchange of information. Every breast-conserving operation must be precisely planned, marked and carried out in a controlled manner. Basic anatomical knowledge is not sufficient enough to perform a prophylactic mastectomy. Implant-based reconstructions change their shape and strength over time and usually lead to follow-up operations. Tissue engineering offers interesting approaches to replace the disadvantages of conventional implants in order to achieve the durability and quality similar to autologous tissue reconstructions.
Increased detection of relevant breast cancers with DBT in mammography screening?
Authors: Weigel Stefanie , Weyer-Elberich Veronika , Hense Hans-Werner , Decker Thomas , Gerß Joachim , Heindel Walter 
Published: September 2024

AbstractScreening with digital breast tomosynthesis plus synthetic mammography (DBT+SM) increases invasive breast cancer detection compared to digital mammography (DM). Since a reduction in breast cancer mortality is largely based on the detection of histological grade 2 or 3 breast cancers, a comparison of the detection rates of invasive breast cancers (iCDR), independent of the stage, of grades 2 or 3, was carried out, taking into account breast density, after screening with DBT+SM vs. DM.The 1:1 randomized, multicenter TOSYMA study recruited participants from 7/2018 to 12/2020 in the German Mammography Screening Program. This explorative subanalysis included 49479 participants in the DBT+SM arm and 49689 participants in the DM arm, with complete documentation including visual density categorization (A/B: non-dense parenchyma, C/D: dense parenchyma).The iCDR of grade 2 or 3 was 5.1 per 1000 women screened with DBT+SM vs. 3.6 ‰ screened with DM (difference +1.5 ‰). In the case of non-dense parenchyma, the corresponding DBT+SM rate was 4.5 ‰ (difference to DM +1.3 ‰), and in dense parenchyma it was 5.7 ‰ (difference to DM +1.7 ‰).The iCDR of grade 1 was 2.1 ‰ with DBT+SM (difference to DM +0.8 ‰). In non-dense parenchyma, the corresponding DBT+SM rate was 1.7 ‰ (difference to DM +0.7 ‰), in dense parenchyma it was 2.6 ‰ (difference to DM +1.0 ‰).When screening with DBT+SM, invasive breast cancer detection rates of grade 2 or 3 tumors are higher than with DM. Detection rates and their differences are also higher in women with dense than non-dense parenchyma. These detection rates and their differences are consistently higher for DBT+SM and DM than those for grade 1 cancers. The explorative analyses of this large, randomized trial indicate that DBT+SM screening increases the detection of prognostically more relevant breast cancers.
Comparison of Ultrasound Findings Associated with Adverse Fetal, Obstetric, and Neonatal Outcomes in Pregestational Type 1 And Type 2 Diabetes: A Systematic Review
Authors: Kraus Alexandria C. , Kucirka Lauren M. , Johnson Julie , AbouNouar Albatoul , Connelly Sean V. , Thel Hannah L. , Kavi Heli S. , Bailey Brazil M. , Fox Madelyn K. , Malloy Kimberly , Conklin Jamie L. , Huprich Erin , Boggess Kim A. 
Published: September 2024

Objective We aimed to summarize the available evidence examining the association between prenatal ultrasound findings and adverse fetal, obstetric, and neonatal outcomes in pregnancies complicated by type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and to evaluate whether the predictive value of ultrasound findings for adverse outcomes varies between T1DM and T2DM pregnancies.
Study Design We conducted a systematic review of the existing literature through August 12, 2024. We included articles in English that reported associations between ultrasound findings and fetal, obstetric, and neonatal outcomes in pregnant people with T1DM and T2DM. The primary outcome of interest was stillbirth; secondary outcomes were neonatal demise, neonatal intensive care unit admission, neonatal hypoglycemia, respiratory distress syndrome, polycythemia, hyperbilirubinemia, organomegaly, electrolyte disturbances, shoulder dystocia, permanent brachial plexus injury, cord gas, Apgar scores, large for gestational age (LGA), small for gestational age (SGA), and preterm birth. Two independent reviewers examined articles at the abstract level and, if eligible, at the full-text level; disagreements were adjudicated by a third reviewer.
Results Of the 2,088 unique citations reviewed, 12 studies met the inclusion criteria describing associations between ultrasound findings and fetal, obstetric, and neonatal outcomes among a total of 1,165 pregnant people with T1DM and 489 pregnant people with T2DM. Most studies (10/12) examined the association between ultrasound measures of growth, including estimated fetal weight and its individual components, abdominal wall thickness, head circumference to abdominal circumference ratio, and birth weight, LGA or SGA. Studies did not examine stillbirth, neonatal demise, or maternal outcomes other than cesarean section.
Conclusion This systematic review synthesizes the available literature on ultrasound risk markers of adverse fetal, obstetric, and neonatal outcomes separately in pregnant people with T1DM and T2DM. We identified very few studies that distinguished between pregnant people with T1DM and T2DM, and the majority focused on surrogate outcomes (e.g., LGA, SGA) of morbidity. Our findings highlight the need for further studies investigating these distinct diseases to provide evidence for antenatal management recommendations.
Key Points
Risikofaktoren für einen schweren COVID-19-Verlauf in einer
Hotspot-Region der ersten und zweiten SARS-CoV-2-Infektionswelle in
Deutschland
Authors: Richter Steffi , Finkenzeller Thomas , Uter Wolfgang , Drexler Hans , Wolfschmidt Anna 
Published: September 2024

Zusammenfassung
Hintergrund In der ersten Welle der SARS-CoV-2-Pandemie war das Klinikum
Weiden ein „Hotspot-Krankenhaus“ und befand sich in einer medizinischen
Ausnahmesituation. Zielsetzung der Studie war die wissenschaftliche Prüfung der
Fragestellung, ob auch für die damals dort Behandelten die bekannten
Risikofaktoren für einen schweren COVID-19-Verlauf verantwortlich waren oder ob
durch die speziellen Bedingungen eines Hotspot-Kollektivs zu Pandemiebeginn
andere Faktoren das Outcome beeinflusst haben könnten.
Methodik In einer retrospektiven Studie wurden Daten von 669 stationär
behandelten Patientinnen und Patienten des Klinikums Weiden ausgewertet, die im
ersten Pandemiejahr 2020 nachweislich mit SARS-CoV-2 infiziert waren. Aus
medizinischen und demographischen Informationen wurden in einer univariaten
Analyse Risikofaktoren für einen schweren COVID-19-Verlauf bestimmt und einer
logistischen Regression zugeführt. Die Regressionsanalyse erfolgte sowohl für
das Gesamtkollektiv als auch getrennt für die Erkrankten aus Welle 1 (März-Juni)
und Welle 2 (Juli-Dezember).
Ergebnisse Im Gesamtkollektiv des Jahres 2020 waren männliches Geschlecht,
Rauchen, ein Alter ab 71 Jahren sowie Depression signifikante Risikofaktoren für
einen schweren COVID-19-Krankheitsverlauf. Andere bekannte Risikofaktoren
konnten im Weidener Kollektiv nicht nachgewiesen werden. Die getrennte
Betrachtung von Welle 1 und 2 (W1 und W2) zeigte, dass das Alter in W1 keinen
entscheidenden Risikofaktor für einen schweren Krankheitsverlauf darstellte, in
W2 hingegen bereits ein Alter ab 61 Jahren das Risiko für einen schweren Verlauf
signifikant erhöhte. Für Erkrankte mit Einweisung in W2 war das Risiko für einen
schweren COVID-19-Verlauf gegenüber Erkrankten mit Einweisung in W1 nahezu
halbiert.
Schlussfolgerung Es ist anzunehmen, dass der Krankheitsverlauf im Weidener
Hotspot-Kollektiv im Wesentlichen von nicht-individuellen Faktoren bestimmt
wurde, wie z. B. der schwierigen Versorgungssituation in einer Hotspot-Klinik zu
Beginn der Pandemie. In Vorbereitung auf künftige Pandemien sollte
berücksichtigt werden, dass auch eine ausreichende Ressourcenbereitstellung
relevant zu einem besseren Outcome der Erkrankten beitragen kann.
Lewis Acid Catalyzed SN2-Type Domino Ring-Opening Cyclization (DROC) of Aziridines with Alkynes: A Synthetic Route to 2,3-Dihydropyrroles
Authors: Ghorai Manas K. , Shukla Dipti , Kashyap Suraj , Singh Bharat , Sharma Amit Kumar , Bhattacharyya Aditya , Rahman Noimur 
Published: September 2024

AbstractA simple strategy for the synthesis of a variety of dihydropyrroles in good to excellent yields via a Lewis acid catalyzed, quaternary ammonium salt mediated SN2-type ring opening followed by cyclization of activated aziridines with alkynes in a domino fashion is described. The formation and the observed stereoselectivities of the products via an SN2-/double SN2-type ring-opening pathway are rationalized by mechanistic studies.