bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using Iron Stable Isotopes to Quantify the Origins of the Cryoconite Iron Materials in Western China and Exploring Controlling Factors
Authors: Dong Zhiwen , Wei Ting , Parteli Eric J. R. , Liu Xiaoli , Ren Jiawen , Shao Yaping 
Published: July 2024

AbstractIron (Fe) has profound impacts on Earth's ecosystem and global biogeochemical cycles. Fe deposited onto glacier surfaces reduces snow and ice albedo, thereby accelerating glacier melting, and supplying downstream ecosystems with dissolved Fe. However, the origins of atmospheric Fe deposition in glacier regions of western China remain unclear. This study presents novel insights into Fe isotopic composition (refer to δ56Fe) and origins, gained from geochemical analysis of large‐scale cryoconite samples collected from glaciers in western China, which encompass the Tibetan Plateau (TP) and the Tianshan Mountains. Results showed that cryoconite δ56Fe ranged from −1.06 ± 0.07‰ to 0.33 ± 0.04‰, regardless of their concentration. Moreover, anomalous δ56Fe values deviating significantly from the upper continental crust values (with an average of 0.09‰) were detected, indicating a significant impact of anthropogenic Fe materials on the investigated glaciers. This impact was particularly prominent in the margin regions of the TP and its surroundings, but was less apparent in the interior and southern of the plateau. Using MixSIAR isotope mixing model, we determined that coal combustion and other anthropogenic combustion sources (such as liquid fuel combustion and steel smelting) contributed to cryoconite Fe in the range of 6.9%–43.1% and 0.8%–23.4%, respectively. Among these, coal combustion was the predominant anthropogenic source of cryoconite Fe in western China's glaciers. Compared with other sink areas in the Northern Hemisphere, glaciers in western China are obviously affected by anthropogenically sourced Fe. This study has significant implications for understanding glacier‐fed downstream ecosystems and the regional biogeochemical cycle.
Eroding Permafrost Coastlines Release Biodegradable Dissolved Organic Carbon to the Arctic Ocean
Authors: Bristol Emily M. , Behnke Megan I. , Spencer Robert G. M. , McKenna Amy , Jones Benjamin M. , Bull Diana L. , McClelland James W. 
Published: July 2024

AbstractCoastal erosion mobilizes large quantities of organic matter (OM) to the Arctic Ocean where it may fuel greenhouse gas emissions and marine production. While the biodegradability of permafrost‐derived dissolved organic carbon (DOC) has been extensively studied in inland soils and freshwaters, few studies have examined dissolved OM (DOM) leached from eroding coastal permafrost in seawater. To address this knowledge gap, we sampled three horizons from bluff exposures near Drew Point, Alaska: seasonally thawed active layer soils, permafrost containing Holocene terrestrial and/or lacustrine OM, and permafrost containing late‐Pleistocene marine‐derived OM. Samples were leached in seawater to compare DOC yields, DOM composition (chromophoric DOM, Fourier transform ion cyclotron resonance mass spectrometry), and biodegradable DOC (BDOC). Holocene terrestrial permafrost leached the most DOC compared to active layer soils and Pleistocene marine permafrost. However, DOC from Pleistocene marine permafrost was the most biodegradable (33 ± 6% over 90 days), followed by DOC from active layer soils (23 ± 5%) and Holocene terrestrial permafrost (14 ± 3%). Permafrost leachates contained relatively more aliphatic and peptide‐like formulae, whereas active layer leachates contained relatively more aromatic formulae. BDOC was positively correlated with nitrogen‐containing and aliphatic formulae, and negatively correlated with polyphenolic and condensed aromatic formulae. Using estimates of eroding OM, we scale our results to estimate DOC and BDOC inputs to the Alaska Beaufort Sea. While DOC inputs from coastal erosion are relatively small compared to rivers, our results suggest that erosion may be an important source of BDOC to the Beaufort Sea when river inputs are low.
Ferroptosis-based advanced therapies as treatment approaches for metabolic and cardiovascular diseases
Authors: Maremonti Francesca , Tonnus Wulf , Gavali Shubhangi , Bornstein Stefan , Shah Ajay , Giacca Mauro , Linkermann Andreas 
Published: July 2024

AbstractFerroptosis has attracted attention throughout the last decade because of its tremendous clinical importance. Here, we review the rapidly growing body of literature on how inhibition of ferroptosis may be harnessed for the treatment of common diseases, and we focus on metabolic and cardiovascular unmet medical needs. We introduce four classes of preclinically established ferroptosis inhibitors (ferrostatins) such as iron chelators, radical trapping agents that function in the cytoplasmic compartment, lipophilic radical trapping antioxidants and ninjurin-1 (NINJ1) specific monoclonal antibodies. In contrast to ferroptosis inducers that cause serious untoward effects such as acute kidney tubular necrosis, the side effect profile of ferrostatins appears to be limited. We also consider ferroptosis as a potential side effect itself when several advanced therapies harnessing small-interfering RNA (siRNA)-based treatment approaches are tested. Importantly, clinical trial design is impeded by the lack of an appropriate biomarker for ferroptosis detection in serum samples or tissue biopsies. However, we discuss favorable clinical scenarios suited for the design of anti-ferroptosis clinical trials to test such first-in-class compounds. We conclude that targeting ferroptosis exhibits outstanding treatment options for metabolic and cardiovascular diseases, but we have only begun to translate this knowledge into clinically relevant applications.
A preoperative dose of the pyridoindole AC102 improves the recovery of residual hearing in a gerbil animal model of cochlear implantation
Authors: Nieratschker Michael , Yildiz Erdem , Gerlitz Matthias , Bera Sujoy , Gadenstaetter Anselm J. , Kramer Anne-Margarethe , Kwiatkowska Monika , Mistrik Pavel , Landegger Lukas D. , Braun Susanne , Schlingensiepen Reimar , Honeder Clemens , Arnoldner Christoph , Rommelspacher Hans 
Published: July 2024

AbstractSensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. In a gerbil animal model of CI, AC102 significantly improves the recovery of hearing thresholds across multiple frequencies and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. In vitro experiments in an ethanol challenged HT22 cell-line revealed significant and dose-responsive anti-apoptotic effects following the treatment of with AC102. Further, AC102 treatment resulted in significant downregulation of the expression of pro-inflammatory cytokines in an organotypic ex vivo model of electrode insertion trauma (EIT). These results suggest that AC102’s effects are likely elicited during the inflammatory phase of EIT and mediated by anti-apoptotic and anti-inflammatory properties, highlighting AC102 as a promising compound for hearing preservation during CI. Moreover, since the inflammatory response in CI shares similarities to that in other etiologies of SNHL, AC102 may be inferred as a potential general treatment option for various inner ear conditions.
DEPDC1 as a metabolic target regulates glycolysis in renal cell carcinoma through AKT/mTOR/HIF1α pathway
Authors: Di Si-chen , Chen Wen-jin , Yang Wei , Zhang Xiang-min , Dong Ke-qin , Tian Yi-jun , Sun Ye , Qian Cheng , Chen Jia-xin , Liu Zi-chang , Gong Zi-xuan , Chu Jian , Zhou Wang , Pan Xiu-wu , Cui Xin-gang 
Published: July 2024

AbstractRenal cell carcinoma (RCC) is considered a “metabolic disease” characterized by elevated glycolysis in patients with advanced RCC. Tyrosine kinase inhibitor (TKI) therapy is currently an important treatment option for advanced RCC, but drug resistance may develop in some patients. Combining TKI with targeted metabolic therapy may provide a more effective approach for patients with advanced RCC. An analysis of 14 RCC patients (including three needle biopsy samples with TKI resistance) revealed by sing-cell RNA sequencing (scRNA-seq) that glycolysis played a crucial role in poor prognosis and drug resistance in RCC. TCGA-KIRC and glycolysis gene set analysis identified DEPDC1 as a target associated with malignant progression and drug resistance in KIRC. Subsequent experiments demonstrated that DEPDC1 promoted malignant progression and glycolysis of RCC, and knockdown DEPDC1 could reverse TKI resistance in RCC cell lines. Bulk RNA sequencing (RNA-seq) and non-targeted metabolomics sequencing suggested that DEPDC1 may regulate RCC glycolysis via AKT/mTOR/HIF1α pathway, a finding supported by protein-level analysis. Clinical tissue samples from 98 RCC patients demonstrated that DEPDC1 was associated with poor prognosis and predicted RCC metastasis. In conclusion, this multi-omics analysis suggests that DEPDC1 could serve as a novel target for TKI combined with targeted metabolic therapy in advanced RCC patients with TKI resistance.
PPAR-γ/NF-kB/AQP3 axis in M2 macrophage orchestrates lung adenocarcinoma progression by upregulating IL-6
Authors: Lin Guofu , Lin Lanlan , Chen Xiaohui , Chen Luyang , Yang Jiansheng , Chen Yanling , Qian Danwen , Zeng Yiming , Xu Yuan 
Published: July 2024

AbstractAquaporin 3 (AQP3), which is mostly expressed in pulmonary epithelial cells, was linked to lung adenocarcinoma (LUAD). However, the underlying functions and mechanisms of AQP3 in the tumor microenvironment (TME) of LUAD have not been elucidated. Single-cell RNA sequencing (scRNA-seq) was used to study the composition, lineage, and functional states of TME-infiltrating immune cells and discover AQP3-expressing subpopulations in five LUAD patients. Then the identifications of its function on TME were examined in vitro and in vivo. AQP3 was associated with TNM stages and lymph node metastasis of LUAD patients. We classified inter- and intra-tumor diversity of LUAD into twelve subpopulations using scRNA-seq analyses. The analysis showed AQP3 was mainly enriched in subpopulations of M2 macrophages. Importantly, mechanistic investigations indicated that AQP3 promoted M2 macrophage polarization by the PPAR-γ/NF-κB axis, which affected tumor growth and migration via modulating IL-6 production. Mixed subcutaneous transplanted tumor mice and Aqp3 knockout mice models were further utilized, and revealed that AQP3 played a critical role in mediating M2 macrophage polarization, modulating glucose metabolism in tumors, and regulating both upstream and downstream pathways. Overall, our study demonstrated that AQP3 could regulate the proliferation, migration, and glycometabolism of tumor cells by modulating M2 macrophages polarization through the PPAR-γ/NF-κB axis and IL-6/IL-6R signaling pathway, providing new insight into the early detection and potential therapeutic target of LUAD.
Glutathione overproduction mediates lymphoma initiating cells survival and has a sex-dependent effect on lymphomagenesis
Authors: H.-Alcántara Alberto , Kourani Omar , Marcos-Jiménez Ana , Martínez-Núñez Patricia , Herranz-Martín Estela , Fuentes Patricia , Toribio María L. , Muñoz-Calleja Cecilia , Iglesias Teresa , Campanero Miguel R. 
Published: July 2024

AbstractLymphoid tumor patients often exhibit resistance to standard therapies or experience relapse post-remission. Relapse is driven by Tumor Initiating Cells (TICs), a subset of tumor cells capable of regrowing the tumor and highly resistant to therapy. Growing cells in 3D gels is a method to discern tumorigenic cells because it strongly correlates with tumorigenicity. The finding that TICs, rather than differentiated tumor cells, grow in 3D gels offers a unique opportunity to unveil TIC-specific signaling pathways and therapeutic targets common to various cancer types. Here, we show that culturing lymphoid cells in 3D gels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells. Treatment with the antioxidant N-acetylcysteine inhibits this lethality and promotes the growth of primary non-tumor lymphoid cells in 3D gels. A subset of lymphoma cells, characterized by an increased abundance of the antioxidant glutathione, escape ROS-induced lethality, a response not seen in non-tumor cells. Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown of GCLC, the GCL catalytic subunit, sharply decreased cell growth in 3D gels and xenografts. Tumor cells from B-cell lymphoma/leukemia patients and λ-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female λ-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients.
The downregulation of SCGN induced by lipotoxicity promotes NLRP3-mediated β-cell pyroptosis
Authors: Ouyang Shuhui , Xiang Sunmin , Wang Xin , Yang Xin , Liu Xuan , Zhang Meilin , Zhou Yiting , Xiao Yang , Zhou Lingzhi , Fan Gang , Yang Jing 
Published: July 2024

AbstractLipotoxicity is a well-established phenomenon that could exacerbate damage to islet β-cells and play a significant role in the development of type 2 diabetes, the underlying mechanisms of which, however, remain unclear. In lipotoxic conditions, secretagogin (SCGN), an EF-hand calcium-binding protein abundantly expressed in islets, is found to undergo downregulation. In light of this, we aim to explore the role of SCGN in lipotoxicity-induced β-cell injury. Our findings show that exposure to ox-LDL in vitro or long-term high-fat diets (HFD) in vivo decreases SCGN expression and induces pyroptosis in β-cells. Moreover, restoring SCGN partially reverses the pyroptotic cell death under ox-LDL or HFD treatments. We have observed that the downregulation of SCGN facilitates the translocation of ChREBP from the cytosol to the nucleus, thereby promoting TXNIP transcription. The upregulation of TXNIP activates the NLRP3/Caspase-1 pathway, leading to pyroptotic cell death. In summary, our study demonstrates that lipotoxicity leads to the downregulation of SCGN expression in islet β-cells, resulting in ChREBP accumulation in the nucleus and subsequent activation of the NLRP3/Caspase-1 pyroptotic pathway. Thus, administering SCGN could be a potential therapeutic strategy to alleviate β-cell damage induced by lipotoxicity in type 2 diabetes.
Spiking attractor model of motor cortex explains modulation of neural and behavioral variability by prior target information
Authors: Rostami Vahid , Rost Thomas , Schmitt Felix Johannes , van Albada Sacha Jennifer , Riehle Alexa , Nawrot Martin Paul 
Published: July 2024

AbstractWhen preparing a movement, we often rely on partial or incomplete information, which can decrement task performance. In behaving monkeys we show that the degree of cued target information is reflected in both, neural variability in motor cortex and behavioral reaction times. We study the underlying mechanisms in a spiking motor-cortical attractor model. By introducing a biologically realistic network topology where excitatory neuron clusters are locally balanced with inhibitory neuron clusters we robustly achieve metastable network activity across a wide range of network parameters. In application to the monkey task, the model performs target-specific action selection and accurately reproduces the task-epoch dependent reduction of trial-to-trial variability in vivo where the degree of reduction directly reflects the amount of processed target information, while spiking irregularity remained constant throughout the task. In the context of incomplete cue information, the increased target selection time of the model can explain increased behavioral reaction times. We conclude that context-dependent neural and behavioral variability is a signum of attractor computation in the motor cortex.
A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry
Authors: Cortese Andrea , Beecroft Sarah J. , Facchini Stefano , Curro Riccardo , Cabrera-Serrano Macarena , Stevanovski Igor , Chintalaphani Sanjog R. , Gamaarachchi Hasindu , Weisburd Ben , Folland Chiara , Monahan Gavin , Scriba Carolin K. , Dofash Lein , Johari Mridul , Grosz Bianca R. , Ellis Melina , Fearnley Liam G. , Tankard Rick , Read Justin , Merve Ashirwad , Dominik Natalia , Vegezzi Elisa , Schnekenberg Ricardo P. , Fernandez-Eulate Gorka , Masingue Marion , Giovannini Diane , Delatycki Martin B. , Storey Elsdon , Gardner Mac , Amor David J. , Nicholson Garth , Vucic Steve , Henderson Robert D. , Robertson Thomas , Dyke Jason , Fabian Vicki , Mastaglia Frank , Davis Mark R. , Kennerson Marina ,   OPDM study group, Oflazer Piraye , Başak Nazli A. , Kayserili Hülya , Yeşil Gözde , Malfatti Edoardo , Lilleker James B. , Wicklund Matthew , Pitceathly Robert D. S. , Brady Stefen , Brais Bernard , Pellerin David , Zuchner Stephan , Danzi Matt C. , Grandis Marina , Comi Giacomo P. , Corti Stefania P. , Abati Elena , Toscano Antonio , Manini Arianna , Ghia Arianna , Tassorelli Cristina , Quartesan Ilaria , Simone Roberto , Rossor Alexander M. , Reilly Mary M. , Carroll Liam , Straub Volker , Udd Bjarne , Chen Zhiyong , Bonne Gisèle , Quinlivan Ros , Hammans Simon , Tucci Arianna , Bahlo Melanie , McLean Catriona A. , Laing Nigel G. , Stojkovic Tanya , Houlden Henry , Hanna Michael G. , Deveson Ira W. , Lockhart Paul J. , Lamont Phillipa J. , Fahey Michael C. , Bugiardini Enrico , Ravenscroft Gianina 
Published: July 2024

AbstractOculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG • CCG repeat motif and a specific pattern of muscle weakness.
Multi-compartmental diversification of neutralizing antibody lineages dissected in SARS-CoV-2 spike-immunized macaques
Authors: Mandolesi Marco , Das Hrishikesh , de Vries Liset , Yang Yiqiu , Kim Changil , Dhinakaran Manojj , Castro Dopico Xaquin , Fischbach Julian , Kim Sungyong , Guryleva Mariia V. , Àdori Monika , Chernyshev Mark , Stålmarck Aron , Hanke Leo , McInerney Gerald M. , Sheward Daniel J. , Corcoran Martin , Hällberg B. Martin , Murrell Ben , Karlsson Hedestam Gunilla B. 
Published: July 2024

AbstractThe continued evolution of SARS-CoV-2 underscores the need to understand qualitative aspects of the humoral immune response elicited by spike immunization. Here, we combine monoclonal antibody (mAb) isolation with deep B cell receptor (BCR) repertoire sequencing of rhesus macaques immunized with prefusion-stabilized spike glycoprotein. Longitudinal tracing of spike-sorted B cell lineages in multiple immune compartments demonstrates increasing somatic hypermutation and broad dissemination of vaccine-elicited B cells in draining and non-draining lymphoid compartments, including the bone marrow, spleen and, most notably, periaortic lymph nodes. Phylogenetic analysis of spike-specific monoclonal antibody lineages identified through deep repertoire sequencing delineates extensive intra-clonal diversification that shaped neutralizing activity. Structural analysis of the spike in complex with a broadly neutralizing mAb provides a molecular basis for the observed differences in neutralization breadth between clonally related antibodies. Our findings highlight that immunization leads to extensive intra-clonal B cell evolution where members of the same lineage can both retain the original epitope specificity and evolve to recognize additional spike variants not previously encountered.
High-throughput sensitive screening of small molecule modulators of microexon alternative splicing using dual Nano and Firefly luciferase reporters
Authors: Best Andrew J. , Braunschweig Ulrich , Wu Mingkun , Farhangmehr Shaghayegh , Pasculescu Adrian , Lim Justin J. , Comsa Lim Caden , Jen Mark , Wang Jenny , Datti Alessandro , Wrana Jeffrey L. , Cordes Sabine P. , Al-awar Rima , Han Hong , Blencowe Benjamin J. 
Published: July 2024

AbstractDisruption of alternative splicing frequently causes or contributes to human diseases and disorders. Consequently, there is a need for efficient and sensitive reporter assays capable of screening chemical libraries for compounds with efficacy in modulating important splicing events. Here, we describe a screening workflow employing dual Nano and Firefly luciferase alternative splicing reporters that affords efficient, sensitive, and linear detection of small molecule responses. Applying this system to a screen of ~95,000 small molecules identified compounds that stimulate or repress the splicing of neuronal microexons, a class of alternative exons often disrupted in autism and activated in neuroendocrine cancers. One of these compounds rescues the splicing of several analyzed microexons in the cerebral cortex of an autism mouse model haploinsufficient for Srrm4, a major activator of brain microexons. We thus describe a broadly applicable high-throughput screening system for identifying candidate splicing therapeutics, and a resource of small molecule modulators of microexons with potential for further development in correcting aberrant splicing patterns linked to human disorders and disease.