bluuebunny/crossref_metadata_2025 huggingface dataset:
Local Time Distribution and Activity Dependence of Extreme Electron Densities in the Auroral D‐Region as an Image of Energy‐Dependent Energetic Electron Precipitation
Authors: Sergeev V. A. , Stepanov N. A. , Ogawa Y. , Rozanov E. V. , Shukhtina M. A.
Published: September 2024

Studying the episodes with the most elevated electron density (Ne) values provides valuable information about spatial distribution and drivers of intense energetic electron (EE) precipitation, which has important space weather implications. By combining EISCAT‐Tromso UHF observations in different modes made in 2001–2021, we survey Ne occurrences and study statistical properties of EE precipitation, producing the highest 10% and 1% of Ne values at the altitudes between 100 and 75 km (corresponding to EE energies of ∼20–∼200 keV). We found that the highest Ne values occur in the nightside‐morning local time sector at the altitudes 90–100 km and in the morning‐noon sector at low altitudes (75–85 km). Although this bimodal pattern could partly be contributed by the suppressed Ne in the dark ionosphere, by analyzing measurements in the twilight conditions at all MLTs together with published patterns of EE precipitation, we argue that a dominance of pre‐noon maximum at low altitudes reflects the enhanced precipitation of >100 keV electrons in this local time sector. At all altitudes (especially below 90 km), the appearance of the highest Ne values favors enhanced auroral activity and shows a strong correlation with fast solar wind (V > 550 km/s) events. These properties mimic the well‐known driving characteristics of energetic electrons. From the correlation of Ne with integral magnetic activity indexes we found that the memory of preceding magnetic activity increases with decreasing altitude, reaching roughly one day at H = 75 km. We discuss the advantages of exploring Ne data at specific altitudes (compared to direct measurements of EE precipitation) to investigate statistically the effects of specific precipitated energy components and the evolution of EE energy spectra.
Impact of Interplanetary Shock on Thermospheric Cooling Emission: A Case Study
Authors: Bag Tikemani , Sivakumar V. , Ogawa Y.
Published: September 2024

Interplanetary (IP) shock is one of the most common phenomena that controls the shape and size of the magnetosphere. It affects the whole magnetosphere‐ionosphere‐thermosphere (MIT) system. We utilized the NO 5.3 m radiative emission, as observed by SABER (Sounding of the Atmosphere using Broadband Emission Radiometry) onboard NASA's TIMED (Thermosphere Ionosphere Mesosphere Energetics Dynamics) satellite, to investigate its response to fast forward shock during 26 January 2017. The high latitude NO emission exhibits a strong enhancement (three times with respect to pre‐event value) during IP shock within 5 hr of onset. We analyzed both the energy dissipation sources and subsequent chemical mechanisms. The Field‐Aligned‐Current observations from Active Magnetosphere and Planetary Response Experiment (AMPERE), EISCAT measurements of Pederson conductivity and the defense Meteorological Satellite Program (DMSP F18) calculated hemispheric power demonstrate a strong intensification. The low energy particle precipitation from DMSP F18 spacecraft shows an early enhancement for energy less than 1 keV. The particle flux of higher energy responds later which remained elevated for longer duration. The thermospheric density and temperature also experience significant variation during IP shock. The NO molecule and temperature displayed an early enhancement. NO density increased by an order of magnitude with respect to the pre‐event value. About 20 increase is noticed in the temperature variation. The atomic oxygen and atomic nitrogen illustrate an early depletion during IP event. The enhanced response of NO cooling to IP shock can be attributed to the combined effects of energy input and subsequent chemical mechanisms.
High discrimination ratio, broadband circularly polarized light photodetector using dielectric achiral nanostructures
Authors: Zhang Guanyu , Lyu Xiaying , Qin Yulu , Li Yaolong , Fan Zipu , Meng Xianghan , Cheng Yuqing , Cao Zini , Xu Yixuan , Sun Dong , Gao Yunan , Gong Qihuang , Lyu Guowei
Published: September 2024

The on-chip measurement of polarization states plays an increasingly crucial role in modern sensing and imaging applications. While high-performance monolithic linearly polarized photodetectors have been extensively studied, integrated circularly polarized light (CPL) photodetectors are still hindered by inadequate discrimination capability. This study presents a broadband CPL photodetector utilizing achiral all-dielectric nanostructures, achieving an impressive discrimination ratio of ~107 at a wavelength of 405 nm. Our device shows outstanding CPL discrimination capability across the visible band without requiring intensity calibration. It functions based on the CPL-dependent near-field modes within achiral structures: under left or right CPL illumination, distinct near-field modes are excited, resulting in asymmetric irradiation of the two electrodes and generating a photovoltage with directions determined by the chirality of the incident light field. The proposed design strategy facilitates ultra-compact CPL detection across diverse materials, structures, and spectral ranges, presenting a novel avenue for achieving high-performance monolithic CPL detection.
Surufatinib plus toripalimab combined with etoposide and cisplatin as first-line treatment in advanced small-cell lung cancer patients: a phase Ib/II trial
Authors: Zhang Yaxiong , Huang Yan , Yang Yunpeng , Zhao Yuanyuan , Zhou Ting , Chen Gang , Zhao Shen , Zhou Huaqiang , Ma Yuxiang , Hong Shaodong , Zhao Hongyun , Zhang Li , Fang Wenfeng
Published: September 2024

There is still room for improvement in first-line treatment of advanced small cell lung cancer (SCLC). This trial firstly investigated efficacy and safety of antiangiogenic therapy (surufatinib) (200 mg, qd, po) plus anti-PD-1 treatment (toripalimab) (240 mg, d1, ivdrip) combined with etoposide (100 mg/m², d1-d3, iv, drip) and cisplatin (25 mg/m², d1-d3, ivdrip) for advanced SCLC as first-line treatment, which has been registered on ClinicalTrials.gov under the identifier NCT04996771. The four-drug regimen was conducted q3w for 4 cycles with maintenance therapy of surufatinib and toripalimab. The primary endpoint was progression-free survival (PFS). The secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. All of the 38 patients were enrolled for safety analysis, while only 35 patients were enrolled for efficacy analysis since loss of efficacy evaluation in 3 cases after treatment. After a median follow-up of 21.3 months, the ORR was 97.1% (34/35), and the DCR and the tumor shrinkage rate were both 100% (35/35). The median PFS was 6.9 months (95% CI: 4.6 m–9.2 m) and the median OS was 21.1 months (95% CI: 12.1 m–30.1 m). The 12-month, 18-month, and 24-month OS rates were 66.94%, 51.39% and 38.54%. The occurrence rate of grade ≥3 treatment-emergent adverse events (TEAEs) was 63.2% (24/38), including neutrophil count decreased (31.6%, 12/38), white blood cell count decreased (23.7%, 9/38) and platelet count decreased (10.5%, 4/38). No unexpected adverse events occurred. This novel four-drug regimen (surufatinib, toripalimab, etoposide plus cisplatin) revealed impressive therapeutic efficacy and tolerable toxicities.
CircSEC24B activates autophagy and induces chemoresistance of colorectal cancer via OTUB1-mediated deubiquitination of SRPX2
Authors: Wang Di , Li Yongge , Chang Weilong , Feng Meina , Yang Yiming , Zhu Xiuxiang , Liu Zhibo , Fu Yang
Published: September 2024

Circular RNAs (circRNAs) are a type of regulatory RNA that feature covalently closed single-stranded loops. Evidence suggested that circRNAs play important roles in the progression and development of various cancers. However, the impact of circRNA on autophagy-mediated progression of colorectal cancer (CRC) remains unclear. The objective of this project was to investigate the influence of circSEC24B on autophagy and its underlying mechanisms in CRC. To validate the presence and circular structure of circSEC24B in CRC cells and tissues, PCR and Sanger sequencing techniques were employed. Drug resistance and invasive phenotype of CRC cells were evaluated using CCK8, transwell, and Edu assays. Gain- and loss-of-function experiments were conducted to assess the effects of circSEC24B and its protein partner on the growth, invasion, and metastasis of CRC cells in vitro and in vivo. Interactions between circSEC24B, OTUB1, and SRPX2 were analyzed through immunofluorescence, RNA-pulldown, and RIP assays. Mass spectrometry analysis was used to identify potential binding proteins of circRNA in CRC cells. Vectors were constructed to investigate the specific structural domain of the deubiquitinating enzyme OTUB1 that binds to circSEC24B. Results showed that circSEC24B expression was increased in CRC tissues and cell lines, and it enhanced CRC cell proliferation and autophagy levels. Mechanistically, circSEC24B promoted CRC cell proliferation by regulating the protein stability of SRPX2. Specifically, circSEC24B acted as a scaffold, facilitating the binding of OTUB1 to SRPX2 and thereby enhancing its protein stability. Additionally, evidence suggested that OTUB1 regulated SRPX2 expression through an acetylation-dependent mechanism. In conclusion, this study demonstrated that circSEC24B activated autophagy and induced chemoresistance in CRC by promoting the deubiquitination of SRPX2, mediated by the deubiquitinating enzyme OTUB1.
Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders
Authors: Cozzi Marta , Magri Stefania , Tedesco Barbara , Patelli Guglielmo , Ferrari Veronica , Casarotto Elena , Chierichetti Marta , Pramaggiore Paola , Cornaggia Laura , Piccolella Margherita , Galbiati Mariarita , Rusmini Paola , Crippa Valeria , Mandrioli Jessica , Pareyson Davide , Pisciotta Chiara , D’Arrigo Stefano , Ratti Antonia , Nanetti Lorenzo , Mariotti Caterina , Sarto Elisa , Pensato Viviana , Gellera Cinzia , Di Bella Daniela , Cristofani Riccardo M. , Taroni Franco , Poletti Angelo
Published: September 2024

Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption. ALS-N999Vfs*40-KIF5A formed SQSTM1/p62-positive inclusions sequestering WT-KIF5A, indicating a gain of toxic function. SPG-R17Q-KIF5A and ALS-N999Vfs*40-KIF5A evidenced a shorter half-life compared to WT-KIF5A, and proteasomal blockage determined their accumulation into detergent-insoluble inclusions. Interestingly, SPG-R280C-KIF5A and ALS-N999Vfs*40-KIF5A both competed for degradation with proteasomal substrates. Finally, NEIMY-C975Vfs*73-KIF5A displayed a similar, but more severe aberrant behaviour compared to ALS-N999Vfs*40-KIF5A; these two mutants share an abnormal tail but cause disorders on the opposite end of KIF5A-linked phenotypic spectrum. Thus, our observations support the pathogenicity of novel KIF5A mutants, highlight abnormalities of recurrent variants, and demonstrate that both unique and shared mechanisms underpin KIF5A-related diseases.
Towards building multilingual language model for medicine
Authors: Qiu Pengcheng , Wu Chaoyi , Zhang Xiaoman , Lin Weixiong , Wang Haicheng , Zhang Ya , Wang Yanfeng , Xie Weidi
Published: September 2024

The development of open-source, multilingual medical language models can benefit a wide, linguistically diverse audience from different regions. To promote this domain, we present contributions from the following: First, we construct a multilingual medical corpus, containing approximately 25.5B tokens encompassing 6 main languages, termed as MMedC, enabling auto-regressive domain adaptation for general LLMs; Second, to monitor the development of multilingual medical LLMs, we propose a multilingual medical multi-choice question-answering benchmark with rationale, termed as MMedBench; Third, we have assessed a number of open-source large language models (LLMs) on our benchmark, along with those further auto-regressive trained on MMedC. Our final model, MMed-Llama 3, with only 8B parameters, achieves superior performance compared to all other open-source models on both MMedBench and English benchmarks, even rivaling GPT-4. In conclusion, in this work, We present a large-scale corpus, a benchmark and a series of models to support the development of multilingual medical LLMs.
Context-dependent agricultural intensification pathways to increase rice production in India
Authors: Nayak Hari Sankar , McDonald Andrew J. , Kumar Virender , Craufurd Peter , Dubey Shantanu Kumar , Nayak Amaresh Kumar , Parihar Chiter Mal , Peramaiyan Panneerselvam , Poonia Shishpal , Tesfaye Kindie , Malik Ram K. , Urfels Anton , Gautam Udham Singh , Silva João Vasco
Published: September 2024

Yield gap analysis is used to characterize the untapped production potential of cropping systems. With emerging large-n agronomic datasets and data science methods, pathways for narrowing yield gaps can be identified that provide actionable insights into where and how cropping systems can be sustainably intensified. Here we characterize the contributing factors to rice yield gaps across seven Indian states, with a case study region used to assess the power of intervention targeting. Primary yield constraints in the case study region were nitrogen and irrigation, but scenario analysis suggests modest average yield gains with universal adoption of higher nitrogen rates. When nitrogen limited fields are targeted for practice change (47% of the sample), yield gains are predicted to double. When nitrogen and irrigation co-limitations are targeted (20% of the sample), yield gains more than tripled. Results suggest that analytics-led strategies for crop intensification can generate transformative advances in productivity, profitability, and environmental outcomes.
A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders
Authors: Lee Arthur S. , Ayers Lauren J. , Kosicki Michael , Chan Wai-Man , Fozo Lydia N. , Pratt Brandon M. , Collins Thomas E. , Zhao Boxun , Rose Matthew F. , Sanchis-Juan Alba , Fu Jack M. , Wong Isaac , Zhao Xuefang , Tenney Alan P. , Lee Cassia , Laricchia Kristen M. , Barry Brenda J. , Bradford Victoria R. , Jurgens Julie A. , England Eleina M. , Lek Monkol , MacArthur Daniel G. , Lee Eunjung Alice , Talkowski Michael E. , Brand Harrison , Pennacchio Len A. , Engle Elizabeth C.
Published: September 2024

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 – as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.
Causal involvement of dorsomedial prefrontal cortex in learning the predictability of observable actions
Authors: Kang Pyungwon , Moisa Marius , Lindström Björn , Soutschek Alexander , Ruff Christian C. , Tobler Philippe N.
Published: September 2024

Social learning is well established across species. While recent neuroimaging studies show that dorsomedial prefrontal cortex (DMPFC/preSMA) activation correlates with observational learning signals, the precise computations that are implemented by DMPFC/preSMA have remained unclear. To identify whether DMPFC/preSMA supports learning from observed outcomes or observed actions, or possibly encodes even a higher order factor (such as the reliability of the demonstrator), we downregulate DMPFC/preSMA excitability with continuous theta burst stimulation (cTBS) and assess different forms of observational learning. Relative to a vertex-cTBS control condition, DMPFC/preSMA downregulation decreases performance during action-based learning but has no effect on outcome-based learning. Computational modeling reveals that DMPFC/preSMA cTBS disrupts learning the predictability, a proxy of reliability, of the demonstrator and modulates the rate of learning from observed actions. Thus, our results suggest that the DMPFC is causally involved in observational action learning, mainly by adjusting the speed of learning about the predictability of the demonstrator.
Revealing real-time 3D in vivo pathogen dynamics in plants by label-free optical coherence tomography
Authors: de Wit Jos , Tonn Sebastian , Shao Mon-Ray , Van den Ackerveken Guido , Kalkman Jeroen
Published: September 2024

Microscopic imaging for studying plant-pathogen interactions is limited by its reliance on invasive histological techniques, like clearing and staining, or, for in vivo imaging, on complicated generation of transgenic pathogens. We present real-time 3D in vivo visualization of pathogen dynamics with label-free optical coherence tomography. Based on intrinsic signal fluctuations as tissue contrast we image filamentous pathogens and a nematode in vivo in 3D in plant tissue. We analyze 3D images of lettuce downy mildew infection (Bremia lactucae) to obtain hyphal volume and length in three different lettuce genotypes with different resistance levels showing the ability for precise (micro) phenotyping and quantification of the infection level. In addition, we demonstrate in vivo longitudinal imaging of the growth of individual pathogen (sub)structures with functional contrast on the pathogen micro-activity revealing pathogen vitality thereby opening a window on the underlying molecular processes.
Private benefit of β-lactamase dictates selection dynamics of combination antibiotic treatment
Authors: Ma Helena R. , Xu Helen Z. , Kim Kyeri , Anderson Deverick J. , You Lingchong
Published: September 2024

β-lactam antibiotics have been prescribed for most bacterial infections since their discovery. However, resistance to β-lactams, mediated by β-lactamase (Bla) enzymes such as extended spectrum β-lactamases (ESBLs), has become widespread. Bla inhibitors can restore the efficacy of β-lactams against resistant bacteria, an approach which preserves existing antibiotics despite declining industry investment. However, the effects of combination treatment on selection for β-lactam resistance are not well understood. Bla production confers both private benefits for resistant cells and public benefits which faster-growing sensitive cells can also exploit. These benefits may be differentially impacted by Bla inhibitors, leading to non-intuitive selection dynamics. In this study, we demonstrate strain-to-strain variation in effective combination doses, with complex growth dynamics in mixed populations. Using modeling, we derive a criterion for the selection outcome of combination treatment, dependent on the burden and effective private benefit of Bla production. We then use engineered strains and natural isolates to show that strong private benefits of Bla are associated with increased selection for resistance. Finally, we demonstrate that this parameter can be coarsely estimated using high-throughput phenotyping of clonal populations. Our analysis shows that quantifying the phenotypic responses of bacteria to combination treatment can facilitate resistance-minimizing optimization of treatment.
The role of water mobility on water-responsive actuation of silk
Authors: Podbevšek Darjan , Jung Yeojin , Khan Maheen K. , Yu Honghui , Tu Raymond S. , Chen Xi
Published: September 2024

Biological water-responsive materials that deform with changes in relative humidity have recently demonstrated record-high actuation energy densities, showing promise as high-performance actuators for various engineering applications. However, there is a lack of theories capable of explaining or predicting the stress generated during water-responsiveness. Here, we show that the nanoscale confinement of water dominates the macroscopic dehydration-induced stress of the regenerated silk fibroin. We modified silk fibroin’s secondary structure, which leads to various distributions of bulk-like mobile and tightly bound water populations. Interestingly, despite these structure variations, all silk samples start to exert force when the bound-to-mobile (B/M) ratio of confined water reaches the same level. This critical B/M water ratio suggests a common threshold above which the chemical potential of water instigates the actuation. Our findings serve as guidelines for predicting and engineering silk’s WR behavior and suggest the potential of describing the WR behavior of biopolymers through confined water.
Pixel to practice: multi-scale image data for calibrating remote-sensing-based winter wheat monitoring methods
Authors: Anderegg Jonas , Tschurr Flavian , Kirchgessner Norbert , Treier Simon , Graf Lukas Valentin , Schmucki Manuel , Caflisch Nicolin , Minguely Camille , Streit Bernhard , Walter Achim
Published: September 2024

Site-specific crop management in heterogeneous fields has emerged as a promising avenue towards increasing agricultural productivity whilst safeguarding the environment. However, successful implementation is hampered by insufficient availability of accurate spatial information on crop growth, vigor, and health status at large scales. Challenges persist particularly in interpreting remote sensing signals within commercial crop production due to the variability in canopy appearance resulting from diverse factors. Recently, high-resolution imagery captured from unmanned aerial vehicles has shown significant potential for calibrating and validating methods for remote sensing signal interpretation. We present a comprehensive multi-scale image dataset encompassing 35,000 high-resolution aerial RGB images, ground-based imagery, and Sentinel-2 satellite data from nine on-farm wheat fields in Switzerland. We provide geo-referenced orthomosaics, digital elevation models, and shapefiles, enabling detailed analysis of field characteristics across the growing season. In combination with rich meta data such as detailed records of crop husbandry, crop phenology, and yield maps, this data set enables key challenges in remote sensing-based trait estimation and precision agriculture to be addressed.
The impact of group membership on punishment versus partner rejection
Authors: Loustau Trystan , Glassman Jacob , Martin Justin W. , Young Liane , McAuliffe Katherine
Published: September 2024

People often display ingroup bias in punishment, punishing outgroup members more harshly than ingroup members. However, the impact of group membership may be less pronounced when people are choosing whether to stop interacting with someone (i.e., partner rejection). In two studies (N = 1667), we investigate the impact of group membership on both response types. Participants were assigned to groups based on a “minimal” groups paradigm (Study 1) or their self-reported political positions (Study 2) and played an incentivized economic game with other players. In this game, participants (Responders) responded to other players (Deciders). In the Punishment condition, participants could decrease the Decider’s bonus pay. In the Partner Rejection condition, participants could reject future interactions with the Decider. Participants played once with an ingroup member and once with an outgroup member. To control for the effects of intent and outcome, scenarios also differed based on the Decider’s Intent (selfish versus fair) and the Outcome (equal versus unequal distribution of resources). Participants punished outgroup members more than ingroup members, however group membership did not influence decisions to reject partners. These results highlight partner rejection as a boundary condition for the impact of group on responses to transgressions.
Modulating the unfolded protein response with ISRIB mitigates cisplatin ototoxicity
Authors: Li Jiang , Rouse Stephanie L. , Matthews Ian R. , Park Yesai , Eltawil Yasmin , Sherr Elliott H. , Chan Dylan K.
Published: September 2024

Cisplatin is a commonly used chemotherapy agent with a nearly universal side effect of sensorineural hearing loss. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate (STS), while beneficial when used in standard risk hepatoblastoma, is associated with reduced survival in disseminated pediatric malignancy, highlighting the need for more specific drugs without potential tumor protective effects. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo, and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin, and UPR marker gene expression and cell death measured. Treatment with ISRIB (Integrated Stress Response InhIBitor), a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested for its ability to reduce apoptosis in HEK cells, hair-cell death in cochlear cultures, and hearing loss using an in vivo mouse model of cisplatin ototoxicity. Finally, to evaluate whether ISRIB might interfere with cisplatin chemoeffectiveness, we tested it in head and neck squamous cell carcinoma (HNSCC) cell-based assays of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose–response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact cisplatin’s cytotoxic effects on HNSCC cell viability, unlike STS. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.
Detection of breast cancer in digital breast tomosynthesis with vision transformers
Authors: Kassis Idan , Lederman Dror , Ben-Arie Gal , Giladi Rosenthal Maia , Shelef Ilan , Zigel Yaniv
Published: September 2024

Digital Breast Tomosynthesis (DBT) has revolutionized more traditional breast imaging through its three-dimensional (3D) visualization capability that significantly enhances lesion discernibility, reduces tissue overlap, and improves diagnostic precision as compared to conventional two-dimensional (2D) mammography. In this study, we propose an advanced Computer-Aided Detection (CAD) system that harnesses the power of vision transformers to augment DBT’s diagnostic efficiency. This scheme uses a neural network to glean attributes from the 2D slices of DBT followed by post-processing that considers features from neighboring slices to categorize the entire 3D scan. By leveraging a transfer learning technique, we trained and validated our CAD framework on a unique dataset consisting of 3,831 DBT scans and subsequently tested it on 685 scans. Of the architectures tested, the Swin Transformer outperformed the ResNet101 and vanilla Vision Transformer. It achieved an impressive AUC score of 0.934 ± 0.026 at a resolution of 384 $$\times$$
×
384. Increasing the image resolution from 224 to 384 not only maintained vital image attributes but also led to a marked improvement in performance (p-value = 0.0003). The Mean Teacher algorithm, a semi-supervised method using both labeled and unlabeled DBT slices, showed no significant improvement over the supervised approach. Comprehensive analyses across different lesion types, sizes, and patient ages revealed consistent performance. The integration of attention mechanisms yielded a visual narrative of the model’s decision-making process that highlighted the prioritized regions during assessments. These findings should significantly propel the methodologies employed in DBT image analysis by setting a new benchmark for breast cancer diagnostic precision.
Enzymatic modification of cotton fibre polysaccharides as an enabler of sustainable laundry detergents
Authors: Yau Hamish C. L. , Byard James , Thompson Lily E. , Malekpour Adam K. , Robson Timothy , Bakshani Cassie R. , Lelanaite Ieva , Willats William G. T. , Lant Neil J.
Published: September 2024

Cotton is the most common natural fibre used in textile manufacture, used alone or with other fibres to create a wide range of fashion clothing and household textiles. Most of these textiles are cleaned using detergents and domestic or commercial washing machines using processes that require many chemicals and large quantities of water and energy. Enzymes can reduce this environmental footprint by enabling effective detergency at reduced temperatures, mostly by directly attacking substrates present in the soils. In the present study, we report the contribution of a cleaning cellulase enzyme based on the family 44 glycoside hydrolase (GH) endo-beta-1,4-glucanase from Paenibacillus polymyxa. The action of this enzyme on textile fibres improves laundry detergent performance in several vectors including soil anti-redeposition, dye transfer inhibition and stain removal. Molecular probes are used to study how this enzyme is targeting both amorphous cellulose and xyloglucan on textile fibres and the relationship between textile surface effects and observed performance benefits.
Understanding inter-individual variability of experimental pain habituation and conditioned pain modulation in healthy individuals
Authors: De Schoenmacker Iara , Scheuren Paulina S. , Sirucek Laura , Lütolf Robin , Gorrell Lindsay M. , Rosner Jan , Curt Armin , Schweinhardt Petra , Hubli Michèle
Published: September 2024

Although reduced experimental pain habituation is proposed as a proxy of diminished endogenous pain modulatory capacity in chronic pain, prior studies show contradictory findings. Even across healthy participants, pain habituation varies substantially, which may relate to another measure of endogenous pain modulation, i.e., conditioned pain modulation (CPM). Hence, this study investigated the relationship between pain habituation and CPM. Pain habituation was assessed in 45 healthy participants between two blocks of 15–20 contact-heat stimuli applied to the hand. Habituation of subjective pain ratings and objective neurophysiological readouts (contact-heat evoked potential (CHEP) and palmar sympathetic skin response (SSR)) was investigated. CPM was assessed by comparing heat pain thresholds before and after hand immersion in a noxious cold (9 °C) and lukewarm water bath (32 °C, to control for repeated measures effects). Pain habituation showed a large variability, with subjective but not objective pain habituation correlating with cold-induced CPM effects (r = 0.50; p = 0.025). This correlation was not observed for ‘true’ CPM effects (corrected for repeated measures effects) nor for CPM effects induced by a lukewarm water bath. These findings suggest that the observed variability in subjective pain habituation may be influenced by both descending endogenous pain modulation and peripheral adaptation processes associated with repeated measures. Objective pain habituation readouts, i.e., CHEPs and SSRs, capture different, complementary aspects of endogenous pain modulation.
A privacy-preserving expert system for collaborative medical diagnosis across multiple institutions using federated learning
Authors: Markkandan S. , Bhavani N. P. G. , Nath Srigitha S.
Published: September 2024

Expert system recommendation assists the healthcare system to develop in real-time monitoring and diagnosis of patient conditions over several healthcare institutions. Privacy concerns, however, present significant problems since patient data leaks can lead to big effects including financial losses for hospitals and invasions of personal privacy for people. To address these issues, the research introduces a privacy-preserving collaborative medical diagnosis (CMD) method on a federated learning (FL). FL maintains patient privacy and data localization by spreading only model parameters, therefore enabling training models on remote datasets. The combination of Partially Homomorphic Cryptosystem (PHC) and Residual Learning based Deep Belief Network (RDBN) ensures an accurate and safe classification of patient physiological data. Experimental results show that the proposed method is successful in maintaining the diagnostic accuracy over numerous healthcare institutions and protecting privacy. The results show that the RDBN and PHC computations requires around 1000 ms and 150 ms, respectively for classification and privacy; the data transmission from the user to server and from server to user is 5 MB and 4 MB, respectively. Finally with a 30% reduction in overhead, the proposed approach offers an average increase in classification accuracy of 10% over multiple datasets.
Population density as the attractor of business to the place
Authors: Kopczewska Katarzyna , Kubara Maria , Kopyt Mateusz
Published: September 2024

Firm location studies traditionally assume that this is business that attracts other business to a given location. They focus on knowledge transfers between the most productive and innovative firms and analyse agglomeration economies arising from matching, learning and sharing mechanisms. We argue that the population density also attracts firms to the place. Therefore, we extend this stream of research by using the concept of economies of density to discuss the effects of the attraction of firms by population. Our study explores the existence of the hierarchical causal mechanism that occurs when 2nd line firms understood as non-innovative, less productive retail and service businesses together with human settlement create an environment that attracts 1st line firms - the most innovative and productive businesses. We show that population density and business agglomeration jointly affect the location of firms in different sectors and should be considered as complementary rather than substitutable attraction factors.
Galectin-9 as a new biomarker of acute-on-chronic liver failure
Authors: Ling Jun , You Shaoli , Chen Weiwei , Yang Xinxin , Xv Yiwen , Zhu Bing
Published: September 2024

Galectin-9 (Gal-9) expression in patients with acute-on-chronic liver failure and its correlation with prognosis remain unclear. This study investigated the relationship between liver failure prognosis and Gal-9 expression analysis in patients with acute-on-chronic liver failure. Patients with acute-on-chronic liver failure attributable to hepatitis B and those with chronic hepatitis B were included in this single-center prospective cohort study. The Gal-9 levels in the acute-on-chronic liver failure group were significantly higher than those in the chronic hepatitis B group, and there was an upregulation of Gal-9 and T-cell immunoglobulin domain and mucin domain-3 expressions in peripheral blood T cells. Gal-9 was localized in the regenerative areas of liver tissues in patients with acute-on-chronic liver failure, co-localizing with Kupffer cells. Kaplan–Meier survival curves showed that patients with Gal-9 levels < 9.6 ng/ml had a worse prognosis, with the area under the receiver operating characteristic curve (AUC-ROC) being similar to that of the Model for End-Stage Liver Disease score. The combined ROC curve of the two had better predictive performance, with an AUC of 0.945. High Gal-9 levels in liver regenerative areas can serve as a prognostic marker, indicating a better prognosis for patients with hepatitis B virus-acute-on-chronic liver failure.
The impact of steatotic liver disease on coronary artery disease through changes in the plasma lipidome
Authors: Björnson Elias , Samaras Dimitrios , Levin Malin , Bäckhed Fredrik , Bergström Göran , Gummesson Anders
Published: September 2024

Steatotic liver disease has been shown to associate with cardiovascular disease independently of other risk factors. Lipoproteins have been shown to mediate some of this relationship but there remains unexplained variance. Here we investigate the plasma lipidomic changes associated with liver steatosis and the mediating effect of these lipids on coronary artery disease (CAD). In a population of 2579 Swedish participants of ages 50 to 65 years, lipids were measured by mass spectrometry, liver fat was measured using computed tomography (CT), and CAD status was defined as the presence of coronary artery calcification (CAC score > 0). Lipids associated with liver steatosis and CAD were identified and their mediating effects between the two conditions were investigated. Out of 458 lipids, 284 were found to associate with liver steatosis and 19 of them were found to also associate with CAD. Two fatty acids, docosatrienoate (22:3n6) and 2-hydroxyarachidate, presented the highest mediating effect between steatotic liver disease and CAD. Other mediators were also identified among sphingolipids and glycerophospholipids, although their mediating effects were attenuated when adjusting for circulating lipoproteins. Further research should investigate the role of docosatrienoate (22:3n6) and 2-hydroxyarachidate as mediators between steatotic liver disease and CAD alongside known risk factors.
Oral administration of cysteine peptides attenuates UV-B-induced skin erythema and pigmentation in humans
Authors: Sakuma Ayako , Kai Yumiko , Yamasaki Yoshimitsu , Tanaka Tomoya , Sakurai Takanobu
Published: September 2024

The oral administration of antioxidants may suppress UV-B-induced skin damage. HITHION YH-15, the extract of Torula yeast (Cyberlindnera jadinii), is rich in cysteine-containing peptides such as reduced and oxidized glutathione (GSH and GSSG), γ-glutamylcysteine (γ-Glu-Cys), and cysteinylglycine (Cys-Gly). These four constituents are termed cysteine peptides. In this study, we investigated the protective effects of cysteine peptides against UV-B in a randomized, placebo-controlled, double-blind, parallel-group study. A total of 90 healthy males and females aged 30–59 years were enrolled and randomized into two groups of 45 individuals each (cysteine peptides (48 mg/day) and placebo). Changes in UV-B-induced erythema and pigmentation were compared between groups after 5 weeks of test food intake. The minimal erythema dose (MED) significantly increased (*p = 0.019) in the cysteine peptides group compared to that in the placebo group, indicating suppression of UV-B-induced erythema. ΔL* value significantly increased (***p < 0.0001) in the cysteine peptides group compared to that in the placebo, indicating pigmentation suppression. We demonstrated that oral administration of cysteine peptides suppresses UV-B-induced erythema and pigmentation through multiple mechanisms. Thus, cysteine peptides may find use as nutricosmetics for maintaining skin health and well-being.

UMIN Clinical Trials Registry ID: UMIN 000050157.
A Data-Centric Approach to improve performance of deep learning models
Authors: Bhatt Nikita , Bhatt Nirav , Prajapati Purvi , Sorathiya Vishal , Alshathri Samah , El-Shafai Walid
Published: September 2024

The Artificial Intelligence has evolved and is now associated with Deep Learning, driven by availability of vast amount of data and computing power. Traditionally, researchers have adopted a Model-Centric Approach, focusing on developing new algorithms and models to enhance performance without altering the underlying data. However, Andrew Ng, a prominent figure in the AI community, has recently emphasized on better (quality) data rather than better models, which has given birth to Data Centric Approach, also known as Data Oriented technique. The transition from model oriented to data oriented approach has rapidly gained momentum within the realm of deep learning. Despite its promise, the Data-Centric Approach faces several challenges, including (a) generating high-quality data, (b) ensuring data privacy, and (c) addressing biases to achieve fairness in datasets. Currently, there has been limited effort in preparing quality data. Our work aims to address this gap by focusing on the generation of high-quality data through methods such as data augmentation, multi-stage hashing to eliminate duplicate instances, to detect and correct noisy labels, using confident learning. The experiments on popular datasets, namely MNIST, Fashion MNIST, and CIFAR-10 were performed by utilizing ResNet-18 as the common framework followed by both Model Centric and Data Centric Approach. Comparative performance analysis revealed that the Data Centric Approach consistently outperformed the Model Centric Approach by a relative margin of at least 3%. This finding highlights the potential for further exploration and adoption of the Data-Centric Approach in various domains such as healthcare, finance, education, and entertainment, where the quality of data could significantly enhance the performance.
Transcriptomic and metabolomic analysis based on different aggressive pecking phenotype in duck
Authors: Zhu Baoguo , Zhu Jinjin , Liu Ai , Yao Bingnong , Liao Fuyou , Yang Shenglin
Published: September 2024

Aggressive pecking is an important welfare and production efficiency issue in poultry farming. The precise mechanisms underlying the occurrence of aggressive pecking remain poorly understood. In this study, we selected Sansui ducks that performed aggressive pecking and ducks that did not perform aggressive pecking from video recordings. Transcriptomic and metabolomic analyses of the whole brains of aggressive pecking ducks and normal ducks revealed 504 differentially expressed genes and 5 differentially altered metabolites (adenosine, guanidinopropionic acid, Met-Leu, Glu-Ile and 5,6,8-trihydroxy-2-methylbenzo[g]chromen-4-one). By jointly analysing the transcriptomics and metabolomics results, we discovered 8 candidate genes (ADCYAP1, GAL, EDN2, EDN1, MC5R, S1PR4, LOC113843450, and IAPP) and one candidate metabolite (adenosine) that regulates aggressive pecking behaviour in ducks. The candidate genes and metabolites may be involved in regulating aggressive pecking behaviour by inducing neurodegeneration and disrupting neural excitatory-inhibitory homeostasis, which in turn affects central nervous system function in aggressive pecking and normal ducks. Our findings provide a new reference for revealing the underlying mechanism of aggressive pecking behaviour in ducks.
A combination of carbonates and Opuntia ficus-indica extract protects esophageal cells against simulated acidic and non-acidic reflux in vitro
Authors: Lehner Martin D. , Scheyhing Ulrike , Elsässer Jens
Published: September 2024

Buffering of stomach acid by antacids is a well-established symptomatic therapy for heartburn. In addition, preparations from prickly pear (Opuntia ficus-indica) have been shown to reduce tissue damage in experimental gastritis models and to attenuate gastrointestinal discomfort in patients. Both active principles have been included in a fixed-combination product for symptomatic treatment of heartburn containing carbonate antacids (CaCO3 and MgCO3) and an extract from Opuntia ficus-indica cladodes. The aim of the study was to characterize the acid neutralization and esophageal cell protective activities of the product and its individual active ingredients in a set of in vitro assays. Acid neutralization was assessed in a simulated stomach model. Protective activity of individual constituents and in combination was analyzed in an esophageal cell line (COLO-680 N) exposed to low pH and deoxycholic acid to simulate acidic and non-acidic reflux challenge. The combination product protected cells against low pH mediated cytotoxicity via acid neutralization by carbonates. Opuntia extract itself and the combination product attenuated bile acid-induced cell irritation as measured by reduced release of proinflammatory interleukin-6 and -8. In conclusion, addition of Opuntia extract to a mineral antacid provides dual protection against acidic and non-acidic simulated reflux challenge.
Environmental impacts of biodegradable microplastics
Authors: Piao Zhengyin , Agyei Boakye Amma Asantewaa , Yao Yuan
Published: September 2024

Biodegradable plastics, perceived as ‘environmentally friendly’ materials, may end up in natural environments. This impact is often overlooked in the literature due to a lack of assessment methods. This study develops an integrated life cycle impact assessment methodology to assess the climate-change and aquatic-ecotoxicity impacts of biodegradable microplastics in freshwater ecosystems. Our results reveal that highly biodegradable microplastics have lower aquatic ecotoxicity but higher greenhouse gas (GHG) emissions. The extent of burden shifting depends on microplastic size and density. Plastic biodegradation in natural environments can result in higher GHG emissions than biodegradation in engineered end of life (for example, anaerobic digestion), contributing substantially to the life cycle GHG emissions of biodegradable plastics (excluding the use phase). A sensitivity analysis identified critical biodegradation rates for different plastic sizes that result in maximum GHG emissions. This work advances understanding of the environmental impacts of biodegradable plastics, providing an approach for the assessment and design of future plastics.
YOD1 sustains NOD2-mediated protective signaling in colitis by stabilizing RIPK2
Authors: Shen Jiangyun , Lou Liyan , Du Xue , Zhou Bincheng , Xu Yanqi , Mei Fuqi , Wu Liangrong , Li Jianmin , Waisman Ari , Ruan Jing , Wang Xu
Published: September 2024

Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis.