bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis
Authors: Tang Stephan , Fuß Anneke , Fattahi Zohreh , Culmsee Carsten 
Published: August 2024

AbstractMitochondria are highly dynamic organelles which undergo constant fusion and fission as part of the mitochondrial quality control. In genetic diseases and age-related neurodegenerative disorders, altered mitochondrial fission-fusion dynamics have been linked to impaired mitochondrial quality control, disrupted organelle integrity and function, thereby promoting neural dysfunction and death. The key enzyme regulating mitochondrial fission is the GTPase Dynamin-related Protein 1 (Drp1), which is also considered as a key player in mitochondrial pathways of regulated cell death. In particular, increasing evidence suggests a role for impaired mitochondrial dynamics and integrity in ferroptosis, which is an iron-dependent oxidative cell death pathway with relevance in neurodegeneration. In this study, we demonstrate that CRISPR/Cas9-mediated genetic depletion of Drp1 exerted protective effects against oxidative cell death by ferroptosis through preserved mitochondrial integrity and maintained redox homeostasis. Knockout of Drp1 resulted in mitochondrial elongation, attenuated ferroptosis-mediated impairment of mitochondrial membrane potential, and stabilized iron trafficking and intracellular iron storage. In addition, Drp1 deficiency exerted metabolic effects, with reduced basal and maximal mitochondrial respiration and a metabolic shift towards glycolysis. These metabolic effects further alleviated the mitochondrial contribution to detrimental ROS production thereby significantly enhancing neural cell resilience against ferroptosis. Taken together, this study highlights the key role of Drp1 in mitochondrial pathways of ferroptosis and expose the regulator of mitochondrial dynamics as a potential therapeutic target in neurological diseases involving oxidative dysregulation.
Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences
Authors: Burren Oliver S. , Dhindsa Ryan S. , Deevi Sri V. V. , Wen Sean , Nag Abhishek , Mitchell Jonathan , Hu Fengyuan , Loesch Douglas P. , Smith Katherine R. , Razdan Neetu , Olsson Henric , Platt Adam , Vitsios Dimitrios , Wu Qiang ,   AstraZeneca Genomics Initiative, Ågren Rasmus , Anderson-Dring Lauren , Atanur Santosh , Baker David , Belvisi Maria , Bohlooly-Y Mohammad , Buvall Lisa , Cameron-Christie Sophia , Cohen Suzanne , Danielson Regina F. , Das Shikta , Davis Andrew , del Angel Guillermo , Ding Wei , Dougherty Brian , Fairhurst-Hunter Zammy , Garg Manik , Georgi Benjamin , Rangel Carmen Guerrero , Harper Andrew , Haefliger Carolina , Hammar Mårten , Hanna Richard N. , Hansen Pernille B. L. , Harrow Jennifer , Henry Ian , Hess Sonja , Hollis Ben , Jiang Xiao , Kundu Kousik , Lai Zhongwu , Lal Mark , Lassi Glenda , Liang Yupu , Lopes Margarida , Lou Eagle , Lythgow Kieren , MacArthur Stewart , Maisuria-Armer Meeta , March Ruth , Martins Carla , Matelska Dorota , Megy Karine , Menzies Rob , Michaëlsson Erik , Middleton Fiona , Mowrey Bill , Muthas Daniel , O’Dell Sean , Oerton Erin , Ohne Yoichiro , Olsson Henric , O’Neill Amanda , Ostridge Kristoffer , Paul Dirk , Prins Bram , Pullman Benjamin , Rae William , Raies Arwa , Reznichenko Anna , Ros Xavier Romero , Sanganee Hitesh , Ben Sidders  , Snowden Mike , Stankovic Stasa , Stevens Helen , Tachmazidou Ioanna , Taiy Haeyam , Tian Lifeng , Underwood Christina , Viollet Coralie , Walentinsson Anna , Wang Lily , Wang Qing-Dong , Wheeler Eleanor , Zehir Ahmet , Zou Zoe , Codd Veryan , Nelson Christopher P. , Samani Nilesh J. , March Ruth E. , Wasilewski Sebastian , Carss Keren , Fabre Margarete , Wang Quanli , Pangalos Menelas N. , Petrovski Slavé 
Published: August 2024

AbstractTelomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis—an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.
Generation and application of novel hES cell reporter lines for the differentiation and maturation of hPS cell-derived islet-like clusters
Authors: Zanfrini Elisa , Bandral Manuj , Jarc Luka , Ramirez-Torres Maria Alejandra , Pezzolla Daniela , Kufrin Vida , Rodriguez-Aznar Eva , Avila Ana Karen Mojica , Cohrs Christian , Speier Stephan , Neumann Katrin , Gavalas Anthony 
Published: August 2024

AbstractThe significant advances in the differentiation of human pluripotent stem (hPS) cells into pancreatic endocrine cells, including functional β-cells, have been based on a detailed understanding of the underlying developmental mechanisms. However, the final differentiation steps, leading from endocrine progenitors to mono-hormonal and mature pancreatic endocrine cells, remain to be fully understood and this is reflected in the remaining shortcomings of the hPS cell-derived islet cells (SC-islet cells), which include a lack of β-cell maturation and variability among different cell lines. Additional signals and modifications of the final differentiation steps will have to be assessed in a combinatorial manner to address the remaining issues and appropriate reporter lines would be useful in this undertaking. Here we report the generation and functional validation of hPS cell reporter lines that can monitor the generation of INS+ and GCG+ cells and their resolution into mono-hormonal cells (INSeGFP, INSeGFP/GCGmCHERRY) as well as β-cell maturation (INSeGFP/MAFAmCHERRY) and function (INSGCaMP6). The reporter hPS cell lines maintained strong and widespread expression of pluripotency markers and differentiated efficiently into definitive endoderm and pancreatic progenitor (PP) cells. PP cells from all lines differentiated efficiently into islet cell clusters that robustly expressed the corresponding reporters and contained glucose-responsive, insulin-producing cells. To demonstrate the applicability of these hPS cell reporter lines in a high-content live imaging approach for the identification of optimal differentiation conditions, we adapted our differentiation procedure to generate SC-islet clusters in microwells. This allowed the live confocal imaging of multiple SC-islets for a single condition and, using this approach, we found that the use of the N21 supplement in the last stage of the differentiation increased the number of monohormonal β-cells without affecting the number of α-cells in the SC-islets. The hPS cell reporter lines and the high-content live imaging approach described here will enable the efficient assessment of multiple conditions for the optimal differentiation and maturation of SC-islets.
Applying MALDI-TOF MS to resolve morphologic and genetic similarities between two Dermacentor tick species of public health importance
Authors: Galletti Maria F. B. M. , Hecht Joy A. , McQuiston John R. , Gartin Jarrett , Cochran Jake , Blocher Bessie H. , Ayres Bryan N. , Allerdice Michelle E. J. , Beati Lorenza , Nicholson William L. , Snellgrove Alyssa N. , Paddock Christopher D. ,   US Tick MALDI-TOF consortium, Kennedy Ashley , Molaei Goudarz , Lado Paula , Foley Janet , Goddard Jerome , Occi James L. , Padgett Kerry , Dykstra Elizabeth , Nolan Melissa , Cortinas Roberto , Sambado Samantha , Fink Sarah , Campbell Scott R. , Romer Yamila 
Published: August 2024

AbstractHard ticks (Acari: Ixodidae) have been historically identified by morphological methods which require highly specialized expertise and more recently by DNA-based molecular assays that involve high costs. Although both approaches provide complementary data for tick identification, each method has limitations which restrict their use on large-scale settings such as regional or national tick surveillance programs. To overcome those obstacles, the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been introduced as a cost-efficient method for the identification of various organisms, as it balances performance, speed, and high data output. Here we describe the use of this technology to validate the distinction of two closely related Dermacentor tick species based on the development of the first nationwide MALDI-TOF MS reference database described to date. The dataset obtained from this protein-based approach confirms that tick specimens collected from United States regions west of the Rocky Mountains and identified previously as Dermacentor variabilis are the recently described species, Dermacentor similis. Therefore, we propose that this integrative taxonomic tool can facilitate vector and vector-borne pathogen surveillance programs in the United States and elsewhere.
Personalized dose selection for the first Waldenström macroglobulinemia patient on the PRECISE CURATE.AI trial
Authors: Blasiak Agata , Tan Lester W. J. , Chong Li Ming , Tadeo Xavier , Truong Anh T. L. , Senthil Kumar Kirthika , Sapanel Yoann , Poon Michelle , Sundar Raghav , de Mel Sanjay , Ho Dean 
Published: August 2024

AbstractThe digital revolution in healthcare, amplified by the COVID-19 pandemic and artificial intelligence (AI) advances, has led to a surge in the development of digital technologies. However, integrating digital health solutions, especially AI-based ones, in rare diseases like Waldenström macroglobulinemia (WM) remains challenging due to limited data, among other factors. CURATE.AI, a clinical decision support system, offers an alternative to big data approaches by calibrating individual treatment profiles based on that individual’s data alone. We present a case study from the PRECISE CURATE.AI trial with a WM patient, where, over two years, CURATE.AI provided dynamic Ibrutinib dose recommendations to clinicians (users) aimed at achieving optimal IgM levels. An 80-year-old male with newly diagnosed WM requiring treatment due to anemia was recruited to the trial for CURATE.AI-based dosing of the Bruton tyrosine kinase inhibitor Ibrutinib. The primary and secondary outcome measures were focused on scientific and logistical feasibility. Preliminary results underscore the platform’s potential in enhancing user and patient engagement, in addition to clinical efficacy. Based on a two-year-long patient enrollment into the CURATE.AI-augmented treatment, this study showcases how AI-enabled tools can support the management of rare diseases, emphasizing the integration of AI to enhance personalized therapy.
Mapping the regulatory landscape for artificial intelligence in health within the European Union
Authors: Schmidt Jelena , Schutte Nienke M. , Buttigieg Stefan , Novillo-Ortiz David , Sutherland Eric , Anderson Michael , de Witte Bart , Peolsson Michael , Unim Brigid , Pavlova Milena , Stern Ariel Dora , Mossialos Elias , van Kessel Robin 
Published: August 2024

AbstractRegulatory frameworks for artificial intelligence (AI) are needed to mitigate risks while ensuring the ethical, secure, and effective implementation of AI technology in healthcare and population health. In this article, we present a synthesis of 141 binding policies applicable to AI in healthcare and population health in the EU and 10 European countries. The EU AI Act sets the overall regulatory framework for AI, while other legislations set social, health, and human rights standards, address the safety of technologies and the implementation of innovation, and ensure the protection and safe use of data. Regulation specifically pertaining to AI is still nascent and scarce, though a combination of data, technology, innovation, and health and human rights policy has already formed a baseline regulatory framework for AI in health. Future work should explore specific regulatory challenges, especially with respect to AI medical devices, data protection, and data enablement.
Oversimplification and misestimation of nitrous oxide emissions from wastewater treatment plants
Authors: Song Cuihong , Zhu Jun-Jie , Willis John L. , Moore Daniel P. , Zondlo Mark A. , Ren Zhiyong Jason 
Published: August 2024

AbstractWastewater treatment is a major source of anthropogenic nitrous oxide (N2O) emissions. However, the current emission estimations rely on a uniform emission factor (EF) proposed by the Intergovernmental Panel on Climate Change based on a limited database suffering from large uncertainties and inaccuracies. To address this limitation, this study expands the database 12-fold and develops a tier-based approach. Our method considers emission variations across spatial scales, treatment processes and monitoring techniques, enabling more-precise estimations. Here, applying this approach to the US database, we highlight the limitations of current estimations based on uniform EFs and quantified the mean wastewater N2O emission in the United States to be 11.6 MMT CO2-eq. The results also reveal the diverse nature of wastewater N2O emissions and underscore the need for a customized approach to inform facility-level N2O emission estimation as well as inform national- and sector-wide greenhouse gases inventories with emphasis on site-specific considerations. Overall, this study provides a tool to recalibrate the estimations of wastewater N2O emissions, which form the foundation of carbon footprint reduction in wastewater treatment.
A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma
Authors: Banu Matei A , Dovas Athanassios , Argenziano Michael G , Zhao Wenting , Sperring Colin P , Cuervo Grajal Henar , Liu Zhouzerui , Higgins Dominique MO , Amini Misha , Pereira Brianna , Ye Ling F , Mahajan Aayushi , Humala Nelson , Furnari Julia L , Upadhyayula Pavan S , Zandkarimi Fereshteh , Nguyen Trang TT , Teasley Damian , Wu Peter B , Hai Li , Karan Charles , Dowdy Tyrone , Razavilar Aida , Siegelin Markus D , Kitajewski Jan , Larion Mioara , Bruce Jeffrey N , Stockwell Brent R , Sims Peter A , Canoll Peter 
Published: August 2024

AbstractGlioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.
Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression
Authors: Javed Zaineb , Shin Dong Hui , Pan Weihua , White Sierra R , Elhaw Amal Taher , Kim Yeon Soo , Kamlapurkar Shriya , Cheng Ya-Yun , Benson J Cory , Abdelnaby Ahmed Emam , Phaëton Rébécca , Wang Hong-Gang , Yang Shengyu , Sullivan Mara L G , St.Croix Claudette M , Watkins Simon C , Mullett Steven J , Gelhaus Stacy L , Lee Nam , Coffman Lan G , Aird Katherine M , Trebak Mohamed , Mythreye Karthikeyan , Walter Vonn , Hempel Nadine 
Published: August 2024

AbstractAberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.
Learned infinite elements for helioseismology
Authors: Fournier D. , Hohage T. , Preuss J. , Gizon L. 
Published: August 2024

Context. Acoustic waves in the Sun are affected by the atmospheric layers, but this region is often ignored in forward models because it increases the computational cost.
Aims. The purpose of this work is to take the solar atmosphere into account without significantly increasing the computational cost.
Methods. We solved a scalar-wave equation that describes the propagation of acoustic modes inside the Sun using a finite-element method. The boundary conditions used to truncate the computational domain were learned from the Dirichlet-to-Neumann operator, that is, the relation between the solution and its normal derivative at the computational boundary. These boundary conditions may be applied at any height above which the background medium is assumed to be radially symmetric.
Results. We show that learned infinite elements lead to a numerical accuracy similar to the accuracy that is obtained for a traditional radiation boundary condition in a simple atmospheric model. The main advantage of learned infinite elements is that they reproduce the solution for any radially symmetric atmosphere to a very good accuracy at low computational cost. In particular, when the boundary condition is applied directly at the surface instead of at the end of the photosphere, the computational cost is reduced by 20% in 2D and by 60% in 3D. This reduction reaches 70% in 2D and 200% in 3D when the computational domain includes the atmosphere.
Conclusions. We emphasize the importance of including atmospheric layers in helioseismology and propose a computationally efficient method to do this.
Avoiding digital addiction
Authors: Posner Michael I. , Rothbart Mary K. , Ghassemzadeh Habibollah 
Published: August 2024

ZUSAMMENFASSUNGIn diesem Beitrag werden die zahlreichen Beiträge von Manfred Spitzer gewürdigt, wobei der Schwerpunkt auf seinem Ansatz zur Sucht bei digitalen Geräten liegt. Wir zeigen, dass die Abhängigkeit von einigen Substanzen das Netzwerk der exekutiven Aufmerksamkeit betrifft. Studien am Menschen zeigen, dass Meditationstraining die Konnektivität in diesem Netzwerk verbessern, und diese Veränderung im Gehirn den Substanzmissbrauch verringern kann. Bei Mäusen verbessert niederfrequente Hirnstimulation die Konnektivität des exekutiven Aufmerksamkeitsnetzwerks und reduziert, wie Meditation, die Angst. Wir argumentieren, dass sowohl Meditationstraining als auch Hirnstimulation die Selbstkontrolle bei Menschen verbessern können, die aufgrund von digitaler Sucht mit anhaltender Aufmerksamkeit zu kämpfen haben. Wir verweisen auch auf einige kognitive und Verhaltenstherapien, die zur Behandlung von Sucht eingesetzt werden. Wir glauben, dass ihre Ergebnisse im Rahmen der Aufmerksamkeitsnetze erklärt werden können. Weitere Forschungsarbeiten sollten dazu dienen, diese Ideen zu testen und sie denjenigen zugänglich zu machen, die aufgrund der übermäßigen Nutzung digitaler Medien Schwierigkeiten haben.
Was Gesundheitseinrichtungen tun können, um die planetare Gesundheit zu fördern
Authors: Mirow Juliane 
Published: August 2024

ZUSAMMENFASSUNGDie Klimakrise schadet sowohl der menschlichen Gesundheit als auch unserem Planeten. Klimatische Veränderungen sind weltweit spürbar. Europa ist der sich am schnellsten erwärmende Kontinent – mit weitreichenden Folgen für die Gesellschaft, Wirtschaft und Ökosysteme weltweit. Die gesundheitlichen Auswirkungen des Klimawandels sind vielfältig. Um die steigende Anzahl gesundheitlicher Probleme, die auf den Klimawandel zurückzuführen sind, zu versorgen, müssen sich Arbeitende in den Gesundheitsberufen der Wechselwirkung zwischen Klima und Gesundheit bewusst sein. Auch das Gesundheitswesen selbst trägt erheblich zum Klimawandel bei. Die Emissionen des Gesundheitssektors akkumulieren zu einem erheblichen ökologischen Fußabdruck. Doch Gesundheitseinrichtungen können Maßnahmen ergreifen, die nicht nur gesundheitsfördernd, sondern auch klimafreundlich sind, und die Gesundheit unseres Planeten schützen.