bluuebunny/crossref_metadata_2025 huggingface dataset:
Incomplete multi-view partial multi-label classification via deep semantic structure preservation
Authors: Li Chaoran , Wu Xiyin , Peng Pai , Zhang Zhuhong , Lu Xiaohuan
Published: July 2024

Recent advances in multi-view multi-label learning are often hampered by the prevalent challenges of incomplete views and missing labels, common in real-world data due to uncertainties in data collection and manual annotation. These challenges restrict the capacity of the model to fully utilize the diverse semantic information of each sample, posing significant barriers to effective learning. Despite substantial scholarly efforts, many existing methods inadequately capture the depth of semantic information, focusing primarily on shallow feature extractions that fail to maintain semantic consistency. To address these shortcomings, we propose a novel Deep semantic structure-preserving (SSP) model that effectively tackles both incomplete views and missing labels. SSP innovatively incorporates a graph constraint learning (GCL) scheme to ensure the preservation of semantic structure throughout the feature extraction process across different views. Additionally, the SSP integrates a pseudo-labeling self-paced learning (PSL) strategy to address the often-overlooked issue of missing labels, enhancing the classification accuracy while preserving the distribution structure of data. The SSP model creates a unified framework that synergistically employs GCL and PSL to maintain the integrity of semantic structural information during both feature extraction and classification phases. Extensive evaluations across five real datasets demonstrate that the SSP method outperforms existing approaches, including lrMMC, MVL-IV, MvEL, iMSF, iMvWL, NAIML, and DD-IMvMLC-net. It effectively mitigates the impacts of data incompleteness and enhances semantic representation fidelity.
Study on the fluidity of the pore-fracture binary system in a tight sandstone reservoir-NMR
Authors: Ge Jing , Zhao Wanchun , Wang Sheng , Hu Song , Chen Guohui
Published: July 2024

Fluid movability in tight sands may not be accurately characterized by pore size-based classification methods solely because of the complex pore structure and heterogeneity in pore size. In this study, on the basis of casting thin slices and scanning electron microscope observation, pore structure was analyzed using mercury injection, NMR, and micron CT to classify and evaluate the tight oil reservoir. The experiment suggest that the quality of tight reservoir is determined by its pore structure, particularly the throat radius, with the microthroat being an essential factor in permeability. Uniquely, we divide the reservoir by Q-cluster with throat radius, displacement pressure, permeability and other parameters. Based on reservoir classification, this study proposed a method for studying the pore size classification of samples on the T2 spectrum by combining CT scanning with mercury intrusion and a NMR experiment. Pore fluids are generally classified into movable fluid and irreducible fluid by one or two NMR T2 cut-offs. The pore size distributions and capillarity boundaries are converted from T2 and mercury injection capillary pressure (MICP). We categorized pores into micropores (T2 < 1), macropores (T2 > 10, with T2 > 300 as fractures), and medium pores (the rest). The saturation of movable fluid and the percentage of micro-fractures can characterize the seepage characteristics of tight reservoirs, which is of great significance for the later periods of oilfield development.
Dynamic Evolution of Concrete Strength Grades: Insights Across Different Ages and Strain Rates
Authors: Wang Shiming , Bai Yunfan , Shen Yan , Zhou Jian , Khandelwal Manoj
Published: July 2024

This paper investigated the dynamic response of plain concrete with three different strength grades, namely C30, C40, and C50, at an early age (3, 7, 14, and 28 days, respectively). Significant patterns were uncovered using a 75-mm-diameter split Hopkinson pressure bar (SHPB) apparatus. Initially, pronounced viscoelastic behaviour was observed in the concrete’s early stages, characterised by a sharp stress-strain curve both before and after reaching its peak. As the concrete matures, stress concentration within the stress-strain curve becomes more pronounced. Additionally, exponential growth in dynamic strength with higher strain rates was observed, while the strain rate index decreased with age. Improving concrete quality was found to reduce the sensitivity of dynamic strength to strain rate. A viscoelastic damage constitutive model was formulated based on experimental analysis to describe the mechanical response effectively. The evolution of concrete properties over time was accurately captured by fitting model parameters to the experimental data. The theoretical stress-strain curves derived from this damage model closely matched experimental curves across various ages.
Robust estimation for kernel exponential families with smoothed total variation distances
Authors: Kanamori Takafumi , Yokoyama Kodai , Kawashima Takayuki
Published: July 2024

In statistical inference, we commonly assume that samples are independent and identically distributed from a probability distribution included in a pre-specified statistical model. However, such an assumption is often violated in practice. Even an unexpected extreme sample called an outlier can significantly impact classical estimators. Robust statistics studies how to construct reliable statistical methods that efficiently work even when the ideal assumption is violated. Recently, some works revealed that robust estimators such as Tukey’s median are well approximated by the generative adversarial net (GAN), a popular learning method for complex generative models using neural networks. GAN is regarded as a learning method using integral probability metrics (IPM), which is a discrepancy measure for probability distributions. In most theoretical analyses of Tukey’s median and its GAN-based approximation, however, the Gaussian or elliptical distribution is assumed as the statistical model. In this paper, we explore the application of GAN-like estimators to a general class of statistical models. As the statistical model, we consider the kernel exponential family that includes both finite and infinite-dimensional models. To construct a robust estimator, we propose the smoothed total variation (STV) distance as a class of IPMs. Then, we theoretically investigate the robustness properties of the STV-based estimators. Our analysis reveals that the STV-based estimator is robust against the distribution contamination for the kernel exponential family. Furthermore, we analyze the prediction accuracy of a Monte Carlo approximation method, which circumvents the computational difficulty of the normalization constant.
Soil bacterial communities affected by land-use types in a small catchment area of the Balaton Uplands (Hungary)
Authors: Borsodi Andrea K. , Megyes Melinda , Zsigmond Tibor , Horel Ágota
Published: July 2024

Changes resulting from different tillage practices can affect the structure of microbial communities, thereby altering soil ecosystems and their functioning. The aim of this study was to explore and compare the physical, chemical properties and bacterial community composition of soils from different land use types (forest, grassland, vineyard, and arable field) in a small catchment. 16S rRNA gene-based amplicon sequencing was used to reveal the taxonomic diversity of summer and autumn soil samples taken from two different slope positions. The greater the anthropogenic impact was on the type of land use, the greater the change was in soil physical and chemical parameters. All sample types were dominated by the phyla Pseudomonadota, Acidobacteriota, Actinobacteriota, Bacteroidota and Verrucomicrobiota. Differences in the relative abundance of various bacterial taxa reflected the different land use types, the seasonality, and the topography. These diversity changes were consistent with the differences in soil properties.

Graphical abstract
Towards Robust Colour Texture Analysis with Limited Training Data
Authors: Shumska Mariya , Wilkinson Michael H. F. , Bunte Kerstin
Published: July 2024

Texture analysis plays an important role in different domains of healthcare, agriculture, and industry, where multi-channel sensors are gaining more attention. This contribution presents an interpretable and efficient framework for texture classification and segmentation that exploits colour or channel information and does not require much data to produce accurate results. This makes such a framework well-suited for medical applications and resource-limited hardware. Our approach builds upon a distance-based generalized matrix learning vector quantization (GMLVQ) algorithm. We extend it with parametrized angle-based dissimilarity and introduce a special matrix format for multi-channel images. Classification accuracy evaluation of various model designs was performed on VisTex and ALOT data, and the segmentation application was demonstrated on an agricultural data set. Our extension of parametrized angle dissimilarity measure leads to better model generalization and robustness against varying lighting conditions than its Euclidean counterpart. The proposed matrix format for multichannel images enhances classification accuracy while reducing the number of parameters. Regarding segmentation, our method shows promising results, provided with a small class-imbalanced training data set. Proposed methodology achieves higher accuracy than prior work benchmarks and a small-scale CNN while maintaining a significantly lower parameter count. Notably, it is interpretable and accurate in scenarios where limited and unbalanced training data are available.
Convergence of power sequences of operators via their stability
Authors: Jabłoński Zenon Jan , Jung Il Bong , Kubrusly Carlos , Stochel Jan
Published: July 2024

This paper is concerned with the convergence of power sequences and stability of Hilbert space operators, where “convergence” and “stability” are considered with respect to weak, strong and norm topologies. It is proved that an operator has a convergent power sequence if and only if it is a (not necessarily orthogonal) direct sum of an identity operator and a stable operator. This reduces the issue of convergence of the power sequence of an operator T to the study of stability of T. The question of when the limit of the power sequence is an orthogonal projection is investigated. Among operators sharing this property are hyponormal and contractive ones. In particular, a hyponormal or a contractive operator with no identity part is stable if and only if its power sequence is convergent. In turn, a unitary operator has a weakly convergent power sequence if and only if its singular-continuous part is weakly stable and its singular-discrete part is the identity. Characterizations of the convergence of power sequences and stability of subnormal operators are given in terms of semispectral measures.
Mitigating ecological footprint in BRICS countries: unveiling the role of disaggregated clean energy, green technology innovation and political stability
Authors: Behera Biswanath , Behera Puspanjali , Sucharita Sanhita , Sethi Narayan
Published: July 2024

BRICS nations as emerging economies have undergone a substantial structural transformation; however, achieving economic growth while sustaining the ecology is a pressing challenge for these economies. Nonetheless, one of the possible ways to achieve ecological sustainability is to promote clean energy use and green innovation backed by a strengthened political system. Thus, this study assesses the effect of disaggregated clean energy use (hydro and nuclear energy), green technology innovation, and political stability on the ecological footprint in BRICS countries from 1993 to 2022 while controlling for the impacts of natural resources rent, population growth, and GDP per capita. Using dynamic fixed effect and CS-ARDL estimators, the outcomes reveal that hydro and nuclear energy use and political stability induce the ecological footprint in BRICS countries. However, the empirical findings indicate that green technology innovation substantially reduces the ecological footprint. Therefore, from a policy perspective, the study encourages policy coordination among BRICS countries to embrace targeted policies to strengthen regulatory frameworks, promote innovations in technological know-how, and encourage the utilization of clean and sustainable energy to foster environmental sustainability.

Graphical Abstract
Study of performance evaluation of various characteristics of a single phase full bridge inverter circuit using surrounded channel junctionless field effect transistor
Authors: Das Namita , Sarma Kaushik Chandra Deva
Published: July 2024

This paper reports the characteristics study of a single phase full bridge power electronic inverter circuit with a new type of technology namely surrounded channel junctionless field effect transistor (SCJLFET) as a switch. The inverter circuit has been designed using mixed mode simulation platform of TCAD device simulator. The transient characteristics for various temperatures and work functions have been analysed. In the steady state analysis the output current and voltage variation with input voltage with various temperatures and work functions have been studied. The power factor variations with gate oxide thickness and dielectric constant of gate dielectric. The simulation and designing process along with pros and cons have been characterized. The SCJLFET would be one of the strongest participants for advanced power electronics technology as a switches, with various virtues of high-speed operation, low power consumption and low budget process integration. It has also been found that single phase full bridge inverter is giving best results when made using SCJLFET.
Calibration of CFOSAT Off‐Nadir SWIM SWH Product Based on CNN‐LSTM Model
Authors: Zhang Rui , Qi Jinpeng , Yan Qiushuang , Fan Chenqing , Yang Yuchao , Zhang Jie , Wan Yong
Published: July 2024

High‐precision observation of significant wave height (SWH) is crucial for marine research. The Surface Waves Investigation and Monitoring (SWIM) aboard the China France Oceanography Satellite (CFOSAT) provides the ocean wave spectrum that allows for the calculation of the off‐nadir SWH parameters, but there exists a certain bias with the in‐situ SWH values. To improve the accuracy of the SWH calculation bias from the off‐nadir 6°, 8°, 10° wave spectra and the whole combined spectrum, this paper establishes a spatio‐temporal hybrid model that combines convolutional neural network (CNN) and long short‐term memory network (LSTM). Additionally, to further correct bias exhibited under high sea state, we introduce a bias correction module based on deep neural network (DNN) to adjust the SWIM off‐nadir SWH greater than 4 m. The experimental results demonstrate a significant enhancement in the accuracy of corrected SWIM off‐nadir SWH, and the best calibration result is 10° with 0.267 m root mean square error (RMSE), and 0.979 correlation coefficient (R) compared with the ERA5 value. We conducted a comprehensive study and analysis on the performance of the proposed model under different wave heights, extreme sea states, and wind and swell regions. Meanwhile, the buoy and altimeters are leveraged to render further evaluation the RMSE of the corrected SWH is less than 0.5 m.
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

Iron (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

Coastal 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

Ferroptosis 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

Sensorineural 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

Renal 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

Aquaporin 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

Lymphoid 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

Lipotoxicity 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

When 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

Oculopharyngodistal 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

The 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

Disruption 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.
AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery
Authors: Xu Yue , Ma Shihao , Cui Haotian , Chen Jingan , Xu Shufen , Gong Fanglin , Golubovic Alex , Zhou Muye , Wang Kevin Chang , Varley Andrew , Lu Rick Xing Ze , Wang Bo , Li Bowen
Published: July 2024

Ionizable lipid nanoparticles (LNPs) are seeing widespread use in mRNA delivery, notably in SARS-CoV-2 mRNA vaccines. However, the expansion of mRNA therapies beyond COVID-19 is impeded by the absence of LNPs tailored for diverse cell types. In this study, we present the AI-Guided Ionizable Lipid Engineering (AGILE) platform, a synergistic combination of deep learning and combinatorial chemistry. AGILE streamlines ionizable lipid development with efficient library design, in silico lipid screening via deep neural networks, and adaptability to diverse cell lines. Using AGILE, we rapidly design, synthesize, and evaluate ionizable lipids for mRNA delivery, selecting from a vast library. Intriguingly, AGILE reveals cell-specific preferences for ionizable lipids, indicating tailoring for optimal delivery to varying cell types. These highlight AGILE’s potential in expediting the development of customized LNPs, addressing the complex needs of mRNA delivery in clinical practice, thereby broadening the scope and efficacy of mRNA therapies.
Electrocatalytic continuous flow chlorinations with iodine(I/III) mediators
Authors: Patra Tuhin , Arepally Sagar , Seitz Jakob , Wirth Thomas
Published: July 2024

Electrochemistry offers tunable, cost effective and environmentally friendly alternatives to carry out redox reactions with electrons as traceless reagents. The use of organoiodine compounds as electrocatalysts is largely underdeveloped, despite their widespread application as powerful and versatile reagents. Mechanistic data reveal that the hexafluoroisopropanol assisted iodoarene oxidation is followed by a stepwise chloride ligand exchange for the catalytic generation of the dichloroiodoarene mediator. Here, we report an environmentally benign iodine(I/III) electrocatalytic platform for the in situ generation of dichloroiodoarenes for different reactions such as mono- and dichlorinations as well as chlorocyclisations within a continuous flow setup.
A solution for 4-propylguaiacol hydrodeoxygenation without ring saturation
Authors: Zhang Zihao , Li Qiang , Wu Xiangkun , Bourmaud Claire , Vlachos Dionisios G. , Luterbacher Jeremy , Bodi Andras , Hemberger Patrick
Published: July 2024

We investigate solvent effects in the hydrodeoxygenation of 4-propylguaiacol (4PG, 166 amu), a key lignin-derived monomer, over Ru/C catalyst by combined operando synchrotron photoelectron photoion coincidence (PEPICO) spectroscopy and molecular dynamics simulations. With and without isooctane co-feeding, ring-hydrogenated 2-methoxy-4-propylcyclohexanol (172 amu) is the first product, due to the favorable flat adsorption configuration of 4PG on the catalyst surface. In contrast, tetrahydrofuran (THF)—a polar aprotic solvent that is representative of those used for lignin solubilization and upgrading—strongly coordinates to the catalyst surface at the oxygen atom. This induces a local steric hindrance, blocking the flat adsorption of 4PG more effectively, as it needs more Ru sites than the tilted adsorption configuration revealed by molecular dynamics simulations. Therefore, THF suppresses benzene ring hydrogenation, favoring a demethoxylation route that yields 4-propylphenol (136 amu), followed by dehydroxylation to propylbenzene (120 amu). Solvent selection may provide new avenues for controlling catalytic selectivity.
Phonon-mediated unconventional superconductivity in rhombohedral stacked multilayer graphene
Authors: Viñas Boström Emil , Fischer Ammon , Profe Jonas B. , Zhang Jin , Kennes Dante M. , Rubio Angel
Published: July 2024

Understanding the origin of superconductivity in correlated two-dimensional materials is a key step in leveraging material engineering techniques for next-generation nanoscale devices. While it is widely accepted that phonons fluctuations only mediate conventional (s-wave) superconductivity, the common phenomenology of superconductivity in Bernal bilayer and rhombohedral trilayer graphene, as well as in a large family of graphene-based moiré systems, suggests a common superconducting mechanism across these platforms. In particular, in all these platforms some superconducting regions violate the Pauli limit, indicating unconventional superconductivity, naively ruling out conventional phonon-mediated pairing as the underlying mechanism. Here we combine first principles simulations with effective low-energy theories to investigate the superconducting mechanism and pairing symmetry in rhombohedral stacked graphene multilayers. We find that phonon-mediated superconductivity explains the main experimental findings, namely the displacement field and doping level dependence of the critical temperature, and the presence of two superconducting regions with different pairing symmetries that depend on the parent normal state. In particular, we find that intra-valley phonon scattering favors a triplet f-wave pairing when combined with electronic correlations stabilizing a spin- and valley-polarized normal state. We also propose a so far unexplored superconducting region at higher hole doping densities nh ≈ 4 × 1012 cm−2, and demonstrate how this highly hole-doped regime can be reached in heterostructures consisting of monolayer α-RuCl3 and rhombohedral trilayer graphene. Our findings promote phonon-mediated pairing as a strong contender to explain superconductivity across a wide range of graphene platforms, and demonstrate that phonons can, in fact, stabilize unconventional superconducting orders.
Flexible adaptive sensing tonometry for medical-grade multi-parametric hemodynamic monitoring
Authors: Deng Mengkang , Du Chentao , Fang Jiayuan , Xu Changshun , Guo Chenhui , Huang Jiantao , Li Kang , Chen Lei , Zhang Yuan-Ting , Chang Yu , Pan Tingrui
Published: July 2024

Continuous hemodynamic monitoring in a wearable means can play a crucial role in managing hypertension and preventing catastrophic cardiovascular events. In this study, we have described the fully wearable tonometric device, referred to as flexible adaptive sensing tonometry (FAST), which is capable of continuous and accurate monitoring of hemodynamic parameters within the medical-grade precision. In particular, the FAST system integrates a 1 × 8 unit array of highly sensitive and highly flexible iontronic sensing (FITS) with 1 mm spatial resolution and a closed-loop motion system. The flexible tonometric architecture has been used to determine the radial arterial position with high sensitivity and high conformability, which simplifies the biaxial searching process of the traditional applanation tonometry into a highly efficient uniaxial applanation while keeping the medical-precision assessments. Importantly, a self-calibration algorithm can be automatically implemented during the applanation process, from which the intra-arterial blood pressure wave can be continuously predicted within the medical-grade precision, and subsequently, multi-parametric hemodynamic analysis can be performed in real-time. Experimental validations on health volunteers have demonstrated that the FAST measurements are all within the required accuracy of the clinical standards for continuous pulse wave assessments, blood pressure monitoring as well as other key hemodynamic parameter evaluations. Therefore, the FAST system, by integrating the flexible iontronic sensing array, provides a real-time, medical-grade hemodynamic monitoring solution in a continuously wearable manner, from which remote patient-centered monitoring can be delivered with both medical precision and convenience.
Comprehensive real time remote monitoring for Parkinson’s disease using Quantitative DigitoGraphy
Authors: Hoffman Shannon L. , Schmiedmayer Paul , Gala Aryaman S. , Wilkins Kevin B. , Parisi Laura , Karjagi Shreesh , Negi Aarushi S. , Revlock Simon , Coriz Christopher , Revlock Jeremy , Ravi Vishnu , Bronte-Stewart Helen
Published: July 2024

People with Parkinson’s disease (PWP) face critical challenges, including lack of access to neurological care, inadequate measurement and communication of motor symptoms, and suboptimal medication management and compliance. We have developed QDG-Care: a comprehensive connected care platform for Parkinson’s disease (PD) that delivers validated, quantitative metrics of all motor signs in PD in real time, monitors the effects of adjusting therapy and medication adherence and is accessible in the electronic health record. In this article, we describe the design and engineering of all components of QDG-Care, including the development and utility of the QDG Mobility and Tremor Severity Scores. We present the preliminary results and insights from an at-home trial using QDG-Care. QDG technology has enormous potential to improve access to, equity of, and quality of care for PWP, and improve compliance with complex time-critical medication regimens. It will enable rapid “Go-NoGo” decisions for new therapeutics by providing high-resolution data that require fewer participants at lower cost and allow more diverse recruitment.