bluuebunny/crossref_metadata_2025_split huggingface dataset:
GPx1 deficiency confers increased susceptibility to ferroptosis in macrophages from individuals with active Crohn’s disease
Authors: Sousa James A. , Callejas Blanca E. , Wang Arthur , Higgins Eve , Herik Aydin , Andonian Natalie , Yousuf Munazza , Colarusso Pina , Raman Maitreyi , McKay Derek M. 
Published: December 2024

AbstractIntestinal cell death is a defining feature of Crohn’s disease (CD), a major form of inflammatory bowel disease. The focus on this aspect of enteric inflammation has mainly been on epithelial cells, while other cell types such as stromal and myeloid cells have received less attention. Hypothesising that decreased macrophage viability in an oxidative environment could be a contributing factor to the pathophysiology of CD, we found that monocyte-derived macrophages from individuals with active CD (but not those in clinical disease remission) have increased sensitivity to cell death induced by H2O2. Molecular biology and pharmacological studies ruled out apoptosis and necroptosis, while increased lipid peroxidation and surface expression of the transferrin receptor implicated ferroptosis as the mechanism of the H2O2-induced cell death: this was supported by suppression of H2O2-cytotoxicity by liproxstatin-1, a pharmacological inhibitor of ferroptosis. Selenoproteins are important antioxidants, and selenium deficiency can be a feature of CD. Despite normal dietary intake of selenium, monocyte-derived macrophages and intestinal macrophages in individuals with CD had decreased protein and/or mRNA expression of the selenoprotein, glutathione peroxidase (GPx)-1. Knockdown of GPx1 in macrophages from healthy volunteers resulted in increased H2O2-induced cell death reminiscent of that observed with macrophages from CD. In summary, monocyte-derived macrophages from individuals with CD have increased susceptibility to H2O2-induced ferroptosis cell death, that may be facilitated, at least in part, by reduced expression of the antioxidant GPx1. We suggest that reduced GPx1 in monocytes recruited to the gut and intestinal macrophages renders these cells vulnerable to reactive oxygen species-evoked ferroptosis cell death and that unraveling the participation of this pathway in Crohn’s disease may reveal novel therapeutic approaches to this chronic condition.
Targeting PPARγ via SIAH1/2-mediated ubiquitin-proteasomal degradation as a new therapeutic approach in luminal-type bladder cancer
Authors: Tu Chih-Chieh , Hsieh Tsung-Han , Chu Cheng-Ying , Lin Yu-Chen , Lin Bo-Jyun , Chen Chun-Han 
Published: December 2024

AbstractBladder cancer (BC) is the second most prevalent genitourinary malignancy worldwide. Despite recent approvals of immune checkpoint inhibitors and targeted therapy for muscle invasive or recurrent BC, options remain limited for patients with non-muscle invasive BC (NMIBC) refractory to Bacillus Calmette-Guérin (BCG) and chemotherapy. NMIBC is more frequently classified as a luminal subtype, in which increased PPARγ activity is a key feature in promoting tumor growth and evasion of immunosurveillance. Cinobufotalin is one of the major compound of bufadienolides, the primary active components of toad venom that has been utilized in the clinical treatment of cancer. We herein focused on cinobufotalin, examining its anticancer activity and molecular mechanisms in luminal-type NMIBC. Our results newly reveal that cinobufotalin strongly suppresses the viability and proliferation of luminal BC cells with minimal cytotoxic effects on normal uroepithelial cells, and exhibits significant antitumor activity in a RT112 xenograft BC model. Mechanistically, our sub-G1-phase cell accumulation, Annexin V staining, caspase-3/8/9 activation, and PARP activation analyses show that cinobufotalin induces apoptosis in luminal-type BC cells. Cinobufotalin significantly inhibited the levels of PPARγ and its downstream targets, as well as lipid droplet formation and free fatty acid levels in RT112 cells. PPARγ overexpression rescued RT112 cells from cinobufotalin-induced apoptosis and mitigated the downregulation of FASN and PLIN4. Finally, we show seemingly for the first time that cinobufotalin promotes SIAH1/2-mediated proteasomal degradation of PPARγ in luminal BC cells. Together, these findings compellingly support the idea that cinobufotalin could be developed as a promising therapeutic agent for treating luminal-type NMIBC.
Tipping the balance of cell death: alternative splicing as a source of MCL-1S in cancer
Authors: Hartman Mariusz L. 
Published: December 2024

AbstractApoptosis-regulating proteins from the B-cell lymphoma-2 (BCL-2) family are of continued interest as they represent promising targets for anti-cancer therapies. Myeloid cell leukemia-1 (MCL-1), which usually refers to the long isoform (MCL-1L) is frequently overexpressed in various types of cancer. However, MCL1 pre-mRNA can also undergo alternative splicing through exon skipping to yield the short isoform, MCL-1S. Regarding its structure and function, MCL-1S corresponds to BCL-2 homology domain 3 (BH3)-only pro-apoptotic proteins in contrast to the pro-survival role of MCL-1L. As cancer cells are usually characterized by the high MCL-1L:MCL-1S ratio, several studies revealed that overexpression of MCL-1S may constitute a new therapeutic approach in cancer and presumably overcome resistance to currently available drugs. Switching the balance towards high levels of MCL-1S is feasible by using inhibitors of alternative splicing-regulating proteins and strategies directly interfering with MCL1 pre-mRNA. Additionally, several compounds were shown to increase MCL-1S levels through unelucidated mechanisms, while diversely affecting the level of MCL-1L isoform. These mechanisms require detailed clarification as the balance between the long and short variants of MCL-1 can also contribute to mitochondrial hyperpolarization. In this respect, the role of MCL-1S in the regulation of apoptosis-unrelated events of the mitochondria physiology, including mitochondria fission and fusion also remains to be determined. In this review, the structure and function of MCL-1S isoform, and MCL-1S-targeting approaches are discussed.
Immune modules to guide diagnosis and personalized treatment of inflammatory skin diseases
Authors: Seremet Teofila , Di Domizio Jeremy , Girardin Antoine , Yatim Ahmad , Jenelten Raphael , Messina Francesco , Saidoune Fanny , Schlapbach Christoph , Bogiatzi Sofia , Minisini Frederic , Garzorz-Stark Natalie , Leuenberger Matthieu , Wüthrich Héloise , Vernez Maxime , Hohl Daniel , Eyerich Stefanie , Eyerich Kilian , Guenova Emmanuella , Paul Carle , Gottardo Raphael , Conrad Curdin , Gilliet Michel 
Published: December 2024

AbstractPrevious advances have identified immune pathways associated with inflammatory skin diseases, leading to the development of targeted therapies. However, there is a lack of molecular approaches that delineate these pathways at the individual patient level for personalized diagnostic and therapeutic guidance. Here, we conduct a cross-comparison of expression profiles from multiple inflammatory skin diseases to identify gene modules defining relevant immune pathways. Seven modules are identified, representing key immune pathways: Th17, Th2, Th1, Type I IFNs, neutrophilic, macrophagic, and eosinophilic. These modules allow the development of a molecular map with high diagnostic efficacy for inflammatory skin diseases and clinico-pathologically undetermined cases. Aligning dominant modules with treatment targets offers a rational framework for treatment selection, improving response rates in both treatment-naïve patients and non-responders to targeted therapies. Overall, our approach offers precision medicine for inflammatory skin diseases, utilizing transcriptional modules to support diagnosis and guide personalized treatment selection.
Low-power scalable multilayer optoelectronic neural networks enabled with incoherent light
Authors: Song Alexander , Murty Kottapalli Sai Nikhilesh , Goyal Rahul , Schölkopf Bernhard , Fischer Peer 
Published: December 2024

AbstractOptical approaches have made great strides towards the goal of high-speed, energy-efficient computing necessary for modern deep learning and AI applications. Read-in and read-out of data, however, limit the overall performance of existing approaches. This study introduces a multilayer optoelectronic computing framework that alternates between optical and optoelectronic layers to implement matrix-vector multiplications and rectified linear functions, respectively. Our framework is designed for real-time, parallelized operations, leveraging 2D arrays of LEDs and photodetectors connected via independent analog electronics. We experimentally demonstrate this approach using a system with a three-layer network with two hidden layers and operate it to recognize images from the MNIST database with a recognition accuracy of 92% and classify classes from a nonlinear spiral data with 86% accuracy. By implementing multiple layers of a deep neural network simultaneously, our approach significantly reduces the number of read-ins and read-outs required and paves the way for scalable optical accelerators requiring ultra low energy.
Nucleosome fibre topology guides transcription factor binding to enhancers
Authors: O’Dwyer Michael R. , Azagury Meir , Furlong Katharine , Alsheikh Amani , Hall-Ponsele Elisa , Pinto Hugo , Fyodorov Dmitry V. , Jaber Mohammad , Papachristoforou Eleni , Benchetrit Hana , Ashmore James , Makedonski Kirill , Rahamim Moran , Hanzevacki Marta , Yassen Hazar , Skoda Samuel , Levy Adi , Pollard Steven M. , Skoultchi Arthur I. , Buganim Yosef , Soufi Abdenour 
Published: December 2024

Abstract
Cellular identity requires the concerted action of multiple transcription factors (TFs) bound together to enhancers of cell-type-specific genes. Despite TFs recognizing specific DNA motifs within accessible chromatin, this information is insufficient to explain how TFs select enhancers1. Here we compared four different TF combinations that induce different cell states, analysing TF genome occupancy, chromatin accessibility, nucleosome positioning and 3D genome organization at the nucleosome resolution. We show that motif recognition on mononucleosomes can decipher only the individual binding of TFs. When bound together, TFs act cooperatively or competitively to target nucleosome arrays with defined 3D organization, displaying motifs in particular patterns. In one combination, motif directionality funnels TF combinatorial binding along chromatin loops, before infiltrating laterally to adjacent enhancers. In other combinations, TFs assemble on motif-dense and highly interconnected loop junctions, and subsequently translocate to nearby lineage-specific sites. We propose a guided-search model in which motif grammar on nucleosome fibres acts as signpost elements, directing TF combinatorial binding to enhancers.
Late Glacial summer paleohydrology across Central Europe
Authors: Prochnow Maximilian , Hepp Johannes , Strobel Paul , Zech Roland , Acharya Sudip , Szidat Sönke , Rius Damien , Millet Laurent , Glaser Bruno , Zech Michael 
Published: December 2024

AbstractIt is generally accepted that a weakening of the North Atlantic thermohaline circulation caused the Younger Dryas cooling. Although the role of seasonality was emphasized previously, this aspect is rarely considered yet, and it remains elusive how this impacted hydroclimate during winters and summers across Central Europe. Here, we coupled biomarker-based δ18O and δ2H from Bergsee in southern Germany to reconstruct deuterium excess as a proxy for evaporation history from the Bølling-Allerød to the Preboreal. We compared this dataset with other biomarker isotope records in Central Europe. They are all lacking a strong isotopic depletion during the Younger Dryas, which is best explained by the summer sensitivity of the biomarker proxies: As Younger Dryas summers were relatively warm, there is an absence of the strong winter cooling signals recorded in annual water isotope records like Greenland or Lake Steißlingen. Lake evaporation at Bergsee together with other paleohydrological reconstructions draw a coherent picture of the Late Glacial hydroclimate, with strong evidence for warm and dry Younger Dryas summers. Rather than a southward shift of the Westerlies during winter, we suggest that a recently proposed feedback mechanism between North Atlantic sea ice extend, strong winter cooling and summer atmospheric blocking serves as a suitable explanation for summer dryness. Additional confidence to the robustness of these biomarker records is provided by the overall agreement of paleohydrological fluctuations during the Preboreal.
Analysis of excessive sheath currents in multiple cable circuits bonded to the same grounding grid
Authors: Li Gen , Zhou Wenjun , Zhou Chengke , Wang Hang , Pan Chen 
Published: December 2024

AbstractIn urban power networks, a common practice is to bond numerous high‐voltage cable circuits to a single grounding grid located in underground tunnels, primarily for reasons of installation convenience. In these situations, excessively high levels of sheath currents were often detected during routine inspections, but no electrical faults were found to be responsible. Previous publications ignored the currents flowing through the shared grounding points into the closed sheath loops of different circuits. In this paper, a mathematical model is established for the current circulating among sheath loops of different circuits, and the factors influencing the circulating current were analysed. The abnormal excessive sheath current is demonstrated to be an increase in the circulating current due to the combined effect of electromagnetic coupling and the shared grounding grid. The circulating current depends on the induced voltages which, in turn, depends on the cable layouts and load currents. The effects of these factors are evaluated in various scenarios. The increase of the circulating current is verified in a field case where four electrically healthy cable circuits sharing the same grounding points were found to have abnormal excessive sheath currents.
A five‐level nested neutral point‐clamped inverter topology
Authors: Obe Desmond O. , Obe Chinedu T. , Odeh Charles I. , Obe Emeka S. 
Published: December 2024

AbstractClassical five‐level nested neutral point‐clamped (5L NNPC) inverter‐leg is a hybrid of the flying‐capacitor and diode‐clamped 5‐L inverter‐leg configurations. Though uniform reduced voltage stress on the constituting switches is evident in 5L NNPC inverter‐leg, trails of the drawbacks of diode‐clamping concept still exist. Compared with the classical 5L NNPC inverter, the state‐of‐the‐art diode‐free 5L NNPC inverter involves no passive power switches and has low conduction losses. However, in this 5L NNPC inverter, two of the eight active switches have blocking voltage rating of 1/2 of the input voltage. Considering this limiting topological feature, an inverter‐leg for 5L NNPC inverter is presented in this paper. In the proposed 5L NNPC inverter‐leg, only one switch has voltage stress of 1/2 of the input voltage. This reduced voltage stress has inverter cost and loss implications. The performances and competitiveness of the 5L NNPC inverter were analysed in detail and demonstrated with a prototype. The blocking voltages of all the constituting power switches; profiles of the flying‐capacitor voltages; and FFT spectrum of line voltage waveform were experimentally obtained. Experimental deactivation and activation of the inverter's capacitor voltages balancing scheme were typified for varying modulation index values.
Identification of ram pressure stripping features in galaxies using citizen science
Authors: Crossett Jacob P. , Jaffé Yara L. , McGee Sean L. , Smith Rory , Bellhouse Callum , Bettoni Daniela , Vulcani Benedetta , Kelkar Kshitija , Lourenço Ana C. C. 
Published: December 2024

Context. Ram pressure stripped galaxies are rare cases of environmental evolution in action. However, our ability to understand these transforming galaxies is limited by the small number of identified galaxies experiencing ram pressure stripping (RPS).
Aims. Our aim is to explore the efficacy of citizen science classifications in identifying ram pressure stripped galaxies, and use this to aid in motivating new potential samples of ram pressure stripped candidates.
Methods. We compiled a sample of over 200 known ram pressure stripped galaxies from the existing literature, with morphological classifications obtained from Galaxy Zoo. We compared these galaxies with magnitude and redshift-matched comparison cluster and field galaxies. Additionally, we created a sample of SDSS cluster galaxies, with morphological classifications similar to known ram pressure stripped galaxies, and compared the fraction of potential new RPS candidates against control samples.
Results. We find that ram pressure stripped galaxies exhibit a higher proportion of ‘odd’ and ‘irregular’ morphological classifications compared to field and cluster comparison samples. This trend is particularly pronounced in galaxies displaying strong optical ram pressure stripping features, but absent from galaxies with only radio tails. We find that SDSS galaxies with Galaxy Zoo classifications consistent with the known RPS galaxies have a higher fraction of visible ram pressure stripping features (19%) compared with other cluster galaxies (12%) when classified by experts. We identify 101 new ram pressure stripping candidate galaxies through these expert classifications.
Conclusions. We demonstrate that indirect morphological classifications from citizen science projects can increase the efficiency with which new stripping candidates are found. Projects such as Galaxy Zoo can aid in the identification of ram pressure stripped galaxies that are key to understanding galaxy evolution in clusters.
Evaluation of Reproducibility of Measurements of Peripapillary Blood Flow with Laser Speckle Flowgraphy in Healthy and POAG Subjects
Authors: von Vopelius-Feldt Alexander , Hamann Timothy , Mayr Andreas , Töteberg-Harms Marc 
Published: December 2024

Abstract
Background Peripapillary blood flow is of diagnostic value in glaucoma.
Material and Methods We investigated the reproducibility of peripapillary blood flow measurements in healthy individuals and in open-angle glaucoma (OAG) patients with the Nidek laser speckle flowgraphy (LSFG)-NAVI system. Blood flow was calculated as the mean of vascular area (MV), mean of tissue area (MT), and mean of overall flow (MA). Intra-rater, inter-session, and inter-rater reproducibility were assessed by determining the intraclass correlation coefficient (ICC) and coefficient of variance (COV).
Results There were 28 healthy subjects and 16 patients with OAG who participated in this prospective single-center trial. ICC and COV of intra-rater reproducibility were assessed in MV as 0.901; 6.424, MT as 0.909; 4.025, and MA as 0.965; 4.168. Inter-session reproducibility yielded ICC and COV values of MV (0.834; 9.223), MT (0.904; 6.215), MA (0.909; 7.069). Inter-rater reproducibility was computed for MV as 0.78; 9.758, MT as 0.890; 7.210, and MA as 0.888; 6.942. There was a significant difference in MA (p = 0.0184) between the healthy individuals (mean 36.299) and the OAG group (mean 24.944), which was not observed for MV (p = 0.0735) or MT (p = 0.1351).
Conclusion High reproducibility of measurements of peripapillary blood flow with the LSFG system was demonstrated in both groups. There is a difference in peripapillary blood flow between healthy controls and OAG patients.
Hereditary Hemorrhagic Telangiectasia: On the Brink of a New Treatment Era?
Authors: Cerrone Antonio , Buscarini Elisabetta , Berté Roberto , Alicante Saverio , Bertolazzi Stefania , Moreschi Olivia , Griffanti Paola , Manfredi Guido 
Published: December 2024

AbstractHereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder with highly variable penetrance, affecting up to 1 in 5,000 individuals. It is characterized by the presence of abnormal blood vessels that can lead to excessive bleeding—most frequently recurrent nosebleeds (epistaxis), skin and mucosal telangiectasias (small, dilated blood vessels), as well as arteriovenous malformations (AVMs) that can form in various organs, particularly the lungs, liver, and brain. HHT is caused by loss-of-function mutations in the BMP9–10/ENG/ALK1/SMAD4 signaling pathway, an important mediator of vascular quiescence. HHT possesses significant challenges for affected individuals, as the complications can range from mild to life-threatening events, depending on the severity and location of the vascular abnormalities. Despite this bleeding disorder being not uncommon, nowadays no specific treatment is as yet available for HHT and most current therapies include repurposed drugs. The aim of this review was to show therapeutic advances on the basis of recent promising clinical trials for HHT.
A Comparative Study of Cancer and Blood Sugar Levels Among Adults as Per NFHS- 4 and NFHS- 5 Surveys in India
Authors: Kaur Amandeep , Kumar Ranjeet , Garg Sonakshi , Kumar Hardik , Kumar Dharmendra 
Published: December 2024

AbstractThe comparison between the current state of these lifestyle disorders and the prevalence of adult lifestyle diseases including diabetes and cancer in India, as reported by NFHS-4 and NFHS-5. Cancer is still the second greatest cause of death worldwide, despite recent advancements in technology and medicine. Northeast India has a greater cancer burden than the rest of the nation, according to a 2020 study released by the Indian National Cancer Registry. In India, an estimated 77 million individuals had diabetes in 2019, and by 2045, that number is expected to rise to over 134 million Program. In accordance with the 2020 WHO study, India had a 30% higher number of cancer-related fatalities (850,000 versus 610,000 deaths) while only reporting 1.32 million new instances of the disease, compared with 2.28 million in the United States of America. In the globe, cancer of the breast is among the most common carcinomas in women to be diagnosed, and it also ranks top in terms of cancer-related deaths. Around the world, the prevalence of cancer of the breast is steadily rising. The primary focus of this study is the high incidence of lifestyle illnesses in the adult Indian population, as measured by NFHS-4 and NFHS-5, including diabetes and cancer. Based on data from the NFHS-4 and NFHS-5 Survey, we discovered that there are growing trends in the percentage of mouth cancer among males (both urban and rural), whereas there are declining trends in the percentage of cervical, oral, and breast cancer in the case of women.