bluuebunny/crossref_metadata_2025 huggingface dataset:
An Overview of TOD Level Assessment Around Rail Transit Stations
Authors: Sun Yajie , Han Baoming , Lu Fang
Published: February 2024

By integrating land use and transportation systems, transit-oriented development (TOD) focuses on transit and land development, development potential, and the balance between transportation and land use. The TOD level assessment not only helps optimize existing TODs but also guides TOD planning. Based on previous literature, methods for assessing TOD around rail transit stations can be roughly divided into three categories: TOD index, the node-place model, and the data envelopment analysis (DEA) model. The TOD index aggregates indicators from different dimensions into a single value for evaluation. The node-place model emphasizes transportation, land use, and the balance between them, as well as expansion factors. And the DEA model is suitable for situations without input indicator weights or consideration of different units of measurement. TOD indicators are the basis of the evaluation, and in both the TOD index and node-place models, indicator weights are mostly determined by using subjective methods. Furthermore, a limited number of studies to date have pre-evaluated the implementation of TOD at rail stations under construction or in planning. This paper aims to assess the level of TOD areas at the rail transit station level, which can help in constructing the evaluation index system, selecting TOD stations, and optimizing them.
The management of grapevine downy mildew: from anti-resistance strategies to innovative approaches for fungicide resistance monitoring
Authors: Toffolatti Silvia Laura , Lecchi Beatrice , Maddalena Giuliana , Marcianò Demetrio , Stuknytė Milda , Arioli Stefania , Mora Diego , Bianco Piero Attilio , Borsa Paolo , Coatti Mauro , Waldner-Zulauf Maya , Borghi Lorenzo , Torriani Stefano FF
Published: February 2024

Efficient grapevine downy mildew control necessitates the implementation of anti-resistance strategies to ensure the ongoing efficacy of available substances and optimal disease control. With the gradual disappearance of multi-site fungicides from the market, reliance on single-site fungicides poses a long-term risk of selecting strains resistant to multiple modes of action. Challenges in disease management encompass selecting optimal spray programs and monitoring field population sensitivity. This study evaluated the efficacy of anti-resistance strategies, including two single-site fungicides (mandipropamid and oxathiapiprolin), on disease control and fungicide sensitivity through a combination of field trials and laboratory tests for the biological and molecular characterization of the pathogen populations over a three-year period (2019–2021). Mandipropamid, a cellulose synthase inhibitor, is used since a long time for downy mildew control, while oxathiapiprolin, an OxySterol Binding Protein homologue Inhibitor, was introduced recently. Field trials demonstrated effective disease control, even in the presence of mandipropamid-resistant strains (with G1105S/V mutations in PvCesA3) and revealed a pronounced selection and spread of resistance to both fungicides in the vineyard where disease pressure was higher. Characterizing pathogen strains remained a significant obstacle in sensitivity monitoring, hindering precise determination of resistance frequencies related to fungicide programs. Traditional techniques, in fact, lack the resolution required for high-throughput isolation and characterization of resistant individuals. To address this challenge, we propose utilizing flow cytometry and fluorescence-activated cell sorting on field sporangia populations, a method able to determine both the number of resistant isolates and isolate pathogen strains in a single assay.
Association between comorbidities associated with diabetes and higher-level functional status in older patients with type 2 diabetes mellitus: a cross sectional study
Authors: Shoji Takuro , Kogure Kenta , Toda Nagisa , Hakoshima Mariko , Katsuyama Hisayuki , Yanai Hidekatsu , Tokunaga Satoshi , Tateoka Korin , Tsuji Taishi , Okura Tomohiro
Published: February 2024

Purpose

To investigate the association between comorbidities associated with diabetes and higher-level functional status as well as the relationship between comorbidities associated with diabetes and higher-level functional status in older patients with type 2 diabetes mellitus who have better social networks.

Methods

Participants were outpatients with type 2 diabetes aged ≥ 65 years, excluding individuals with severe cardiovascular or respiratory illness, hyperglycaemic crisis, type 1 diabetes, or diabetic foot. The Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) was used to evaluate the higher-level functional status. A TMIG-IC score of ≤ 9, instrumental activities of daily living (IADL) ≤ 4, intellectual activity or social role ≤ 3 were defined as decline in higher-level functional status. The comorbidities investigated included peripheral neuropathy, retinopathy, nephropathy, cognitive impairment, depression, frailty, sarcopenia, low muscle strength, stroke, heart disease, and arthritis.

Results

The analysis included 198 patients (mean age 75.9 ± 5.7 years, male 60.1%). After adjusting for potential confounders, depression was associated with TMIG-IC (Prevalence ratio (PR) 2.34, 95% confidence interval (CI) 1.44–3.82), low muscle strength was associated with IADL (PR 2.85, 95% CI 1.30–6.27), and frailty was associated with intellectual activity (PR 1.38, 95% CI 1.10–1.74). In the model with social networks added as a confounder, the relationship between depression or low muscle strength and higher-level functional status was not statistically significant.

Conclusion

Comorbidities of depression and low muscle strength for older patients with type 2 diabetes mellitus increase the risk of malfunctioning of higher-level functional status. Increased interactions with family, friends and neighbours may reduce this event.
Optimizing Mesh to Improve the Triangular Expansion Algorithm for Computing Visibility Regions
Authors: Mikula Jan , Kulich Miroslav
Published: February 2024

This paper addresses the problem of improving the query performance of the triangular expansion algorithm (TEA) for computing visibility regions by finding the most advantageous instance of the triangular mesh, the preprocessing structure. The TEA recursively traverses the mesh while keeping track of the visible region—the set of all points visible from a query point in a polygonal world. We show that the measured query time is approximately proportional to the number of triangle edge expansions during the mesh traversal. We propose a new type of triangular mesh that minimizes the expected number of expansions assuming the query points are drawn from a known probability distribution. We design a heuristic method to approximate the mesh and evaluate the approach on many challenging instances that resemble real-world environments. The proposed mesh improves the mean query times by 12–16% compared to the reference constrained Delaunay triangulation. The approach is suitable to boost offline applications that require computing millions of queries without addressing the preprocessing time. The implementation is publicly available to replicate our experiments and serve the community.
Data Augmentation for Offline Handwritten Text Recognition: A Systematic Literature Review
Authors: de Sousa Neto Arthur Flor , Bezerra Byron Leite Dantas , de Moura Gabriel Calazans Duarte , Toselli Alejandro Héctor
Published: February 2024

Offline Handwritten Text Recognition (HTR) systems concern the automatic recognition and transcription of handwritten text from scanned images to digital media. Recently, HTR research field has become increasingly important due to the growing need for digitizing documents and automating data entry across various industries. However, achieving satisfactory results depend on the amount of available samples to train an optical model. Creating and labeling large enough datasets for this purpose often require significant time and effort, that in some situations may be impractical. To address this problem, data augmentation approaches are commonly used as an essential component of HTR systems. In this way, the present work aims to identify, explore, and analyze the scope of data augmentation approaches for offline HTR systems. Furthermore, we detailed our research protocol and answered four pertinent research questions, which enabled us to discuss trends and possible gaps. A search was conducted across five scientific databases, focusing on papers published between 2012 and 2023. The search yielded 976 primary papers, with 32 meeting the criteria for inclusion in this review. Our results indicate that handwriting synthesis is an emerging research field, and we observed that Digital Image Processing (DIP) is still widely used as an image generator. Nevertheless, the application of Generative Adversarial Networks (GAN) has gained traction in recent years owing to its impressive ability to synthesize images of handwritten text with arbitrary style and content. In addition, we explored and analyzed the most commonly used datasets and text recognition levels in the selected works.
Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe
Authors: Davenport Colleen , Gravel Patricia , Wang Yamei , Williams Setareh A. , Wieland Alethea , Mitlak Bruce
Published: February 2024

Real-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.
The electrode strategy and its coordination mechanism in constructed wetland-microbial fuel cell (CW-MFC): a review
Authors: An Rongdi , Guan Jiunian , Li Gaoxiang , Li Zhuoyu , Sheng Lianxi , Bian Hongfeng , Lu Nan
Published: February 2024

The electrode played an essential role in the operation of CW-MFC system due to its synergistic effect, and the development of electrode strategy has promoted the application of CW-MFC since 2012. In this paper, according to the material and the quantity, the electrode types in CW-MFC were distinctly divided into unified model, composited model, modified model, and multi-electrodes model combined with non-conductive or conductive particle. Different electrode strategies were provided to improve the performance of CW-MFC towards electricity generation, removal of pollutants, and control of greenhouse gas emission, and the coordination mechanism was further reviewed. Furthermore, the development process of the electrode strategy was summarized, and the low-cost, sustainable, and innovated electrode materials were emphatically recommended. For the scale-up application, multi-electrode model was systematically reviewed based on the optimizing of the material, shape, spacing distance, and connection type of electrode. This review may provide guidance to maximize the advantages of CW-MFC applications.

Graphical Abstract
Impacts of Climate Change on Coastal Hydrodynamics Around a Headland and Potential Headland Sediment Bypassing
Authors: Xie Danghan , Hughes Zoe , FitzGerald Duncan , Tas Silke , Asik Tansir Zaman , Fagherazzi Sergio
Published: February 2024

Shorelines face growing threats due to climate change and diminishing sand supply. Coastal headlands, common rocky features along coastlines, are crucial in shaping hydrodynamics and sediment transport. Yet, the influence of future climate conditions, including sea‐level rise (SLR) and intensified storm energy on complex shorelines with headlands has remained relatively unexplored. In this study, we model changes in hydrodynamics and headland bypassing under different SLR and higher storm wave scenarios. Our findings reveal the formation of circulation cells on both sides of a headland, where wave energy converges around the headland zone. Future climate conditions result in larger storm waves on the beach. However, SLR enhances nearshore currents through a landward shifting of the circulation cells, while higher storm waves intensify offshore flow currents due to the seaward movement of the cells. This effect, in turn, increases the potential for headland sediment bypassing.
A Spatially Explicit Uncertainty Analysis of the Air‐Sea CO2 Flux From Observations
Authors: Jersild Annika , Landschützer Peter
Published: February 2024

In order to understand the oceans role as a global carbon sink, we must accurately quantify the amount of carbon exchanged at the air‐sea interface. A widely used machine learning neural network product, the SOM‐FFN, uses observations to reconstruct a monthly, 1° × 1° global CO2 flux estimate. However, uncertainties in neural network and interpolation techniques can be large, especially in seldom‐sampled regions. Here, we present a three‐dimensional (latitude, longitude, time) gridded product for our SOM‐FFN observational data set consisting of uncertainties (pCO2 mapping, transfer velocity, wind) and biases (pCO2 mapping). We find that polar regions are dominated by uncertainty from gas exchange transfer velocity, with an average 48.7% contribution. In contrast, for subtropical regions, wind product choice contributes an average 50.0%. Regions with fewer observations correlate with higher uncertainty and biases, illustrating the importance of maintaining and expanding existing measurements.
Seasonal and Interannual Variability Between Upper Ocean Processes and the Slope Current in the Region Around the Cosmonauts Sea Off East Antarctica
Authors: Yang Shikai , Zhou Meng , Cheng Xuhua
Published: February 2024

The impacts of large‐scale climate variability on the current system and meridional transport in the Cosmonauts Sea off East Antarctica are studied by employing the satellite‐observed absolute dynamic topography (ADT) data and reanalysis hydrographic data. Three currents converge in the Cosmonauts Sea: the Antarctic Circumpolar Current (ACC), the Weddell Gyre Eastern Branch (WGeb) and the Antarctic Slope Current (ASC) containing the Antarctic Slope Front (ASF) topographically locked in the slope region. Strong seasonal and interannual variations are associated with these currents. The ACC and ASC are both stronger in autumn and weaker in spring and summer, while the WGeb extends eastward in winter and retreats in summer. On the interannual timescale, the Southern Annular Mode (SAM) reinforces the westerlies during its positive phase, pushing the ACC southward and suppressing westward ASC, and vice versa. The results on related mechanisms suggest the significant barotropic modulations induced by the winds on ocean dynamics from both the sea surface and interior ocean. The westerlies could affect the meridional sea level gradient through Ekman transport convergence, inducing the geostrophic adjustment of currents. Moreover, the vorticity input from the wind field produces meridional water transport under the topographic and planetaryβ‐effects, potentially influencing the structure of the ASF and associated ASC. This frontal adjustment is superimposed on the background barotropic variations and causes strong local responses of the currents to the remote wind forcing, which indicates a propagation of variability signals from large‐scale barotropic circulations to frontal‐scale baroclinic currents in the ocean interior.
Analysis of Trapped Small‐Scale Internal Gravity Waves Automatically Detected in Satellite Imagery
Authors: Vicari R. , Stephan C. C. , Lane T. P. , Huang Y.
Published: February 2024

In water vapor‐sensitive satellite imagery, small‐scale wave‐like perturbations of brightness temperature can be attributed to the presence of trapped internal waves in the troposphere. We present a method for detecting these local perturbations with wavelengths of about 10 km and apply it to imagery from the Advanced Baseline Imager on board the geostationary satellite GOES‐16. The algorithm allows us to analyze 4 years of sub‐hourly data in the southern part of the tropical eastern Pacific, where only a relatively low amount of medium and high clouds obscures the scene. By combining a measure of wave activity/trapping with ERA5 reanalysis data, we connect the occurrence of trapping with the presence of an increased upper‐tropospheric wind shear. This connection is more evident during December, January and February, when upper‐tropospheric jets are more likely. Our work supports existing case and model studies and is a step forward in the statistical and automated analysis of trapped small‐scale internal waves in the atmosphere.
The Evolutions and Large‐Scale Mechanisms of Summer Stratospheric Ozone Intrusion Across Global Hotspots
Authors: Lee J. , Wu Y. , Wang X.
Published: February 2024

Stratospheric ozone intrusions can have a significant impact on regional near‐surface ozone levels. Especially in summer, intrusions can contribute to extreme ozone events because of preexisting high ozone levels near the surface and cause serious health issues. Considering the increasing trend of surface ozone level, an understanding of stratospheric ozone intrusion is necessary. From a 19‐year Whole Atmosphere Community Climate Model, version 6 simulation and a stratospheric origin ozone tracer, we identify the global hotspots of stratospheric intrusions based on extreme tracer concentrations near the surface: North America, Africa, the Mediterranean, and the Middle East. We investigate the common underlying large‐scale mechanisms of the stratospheric intrusions over the identified hotspots from the lower stratosphere to the lower troposphere. From the trajectory analysis, we find that the upper‐level jet drives isentropic mixing near the jet axis and initiates stratospheric ozone intrusion. Subsequently, climatological descent at the lower troposphere brings the ozone down to the surface, which explains the spatial preference of summertime stratospheric intrusion events.
The Not-So-Silent Depths
Authors: Bayrakci Gaye , Klingelhoefer Frauke
Published: February 2024

A new book reveals that ocean depths are far from silent voids, but are actually alive with noise.
Elevating the field for applying neuroimaging to individual patients in psychiatry
Authors: Roalf David R. , Figee Martijn , Oathes Desmond J.
Published: February 2024

Although neuroimaging has been widely applied in psychiatry, much of the exuberance in decades past has been tempered by failed replications and a lack of definitive evidence to support the utility of imaging to inform clinical decisions. There are multiple promising ways forward to demonstrate the relevance of neuroimaging for psychiatry at the individual patient level. Ultra-high field magnetic resonance imaging is developing as a sensitive measure of neurometabolic processes of particular relevance that holds promise as a new way to characterize patient abnormalities as well as variability in response to treatment. Neuroimaging may also be particularly suited to the science of brain stimulation interventions in psychiatry given that imaging can both inform brain targeting as well as measure changes in brain circuit communication as a function of how effectively interventions improve symptoms. We argue that a greater focus on individual patient imaging data will pave the way to stronger relevance to clinical care in psychiatry. We also stress the importance of using imaging in symptom-relevant experimental manipulations and how relevance will be best demonstrated by pairing imaging with differential treatment prediction and outcome measurement. The priorities for using brain imaging to inform psychiatry may be shifting, which compels the field to solidify clinical relevance for individual patients over exploratory associations and biomarkers that ultimately fail to replicate.
PRL-mediated STAT5B/ARRB2 pathway promotes the progression of prostate cancer through the activation of MAPK signaling
Authors: Yang Tao , Chi Yongnan , Wang Xin’an , Xu Chengdang , Chen Xi , Liu Ying , Huang Shengsong , Zhu Xuyou , Zhang Haoyang , Zhuo Hui , Wu Denglong
Published: February 2024

Previous study showed that higher expression of prolactin (PRL) was found in CRPC samples compared with hormone-naive prostate cancer (HNPC) and benign prostatic hyperplasia (BPH) samples. We further investigate the function of PRL in prostate cancer (PCa) and explored its downstream effects. We found heterogeneous expression of the PRLR in clinical prostate samples. The VCaP and 22Rv1 cells exhibited PRLR expression. Among the downstream proteins, STAT5B was the dominant subtype in clinical samples and cell lines. Human recombinant PRL stimulation of PCa cells with PRLR expression resulted in increased phosphorylation of STAT5B(pSTAT5B) and progression of PCa in vitro and in vivo, and STAT5B knockdown can suppress the malignant behavior of PCa. To understand the mechanism further, we performed Bioinformatic analysis, ChIP qPCR, and luciferase reporter gene assay. The results revealed that ARRB2 was the transcription target gene of STAT5B, and higher expression of ARRB2 was related to higher aggression and poorer prognosis of PCa. Additionally, Gene set enrichment analysis indicated that higher expression of ARRB2 was significantly enriched in the MAPK signaling pathway. Immunohistochemistry (IHC) demonstrated elevated pSTAT5B, ARRB2, and pERK1/2 expression levels in CRPC tissues compared to HNPC and BPH. Mechanically, ARRB2 enhanced the activation of the MAPK pathway by binding to ERK1/2, thereby promoting the phosphorylation of ERK1/2 (pERK1/2). In conclusion, our study demonstrated that PRL stimulation can promote the progression of PCa through STAT5B/ARRB2 pathway and activation of MAPK signaling, which can be suppressed by intervention targeting STAT5B. Blockade of the STAT5B can be a potential therapeutic target for PCa.
1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature
Authors: Tonelotto Valentina , Costa-Garcia Marcel , O’Reilly Eve , Smith Kaelin Francis , Slater Kayleigh , Dillon Eugene T. , Pendino Marzia , Higgins Catherine , Sist Paola , Bosch Rosa , Passamonti Sabina , Piulats Josep M. , Villanueva Alberto , Tramer Federica , Vanella Luca , Carey Michelle , Kennedy Breandán N.
Published: February 2024

Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM.
The dynamic genetic determinants of increased transcriptional divergence in spermatids
Authors: Panten Jasper , Heinen Tobias , Ernst Christina , Eling Nils , Wagner Rebecca E. , Satorius Maja , Marioni John C. , Stegle Oliver , Odom Duncan T.
Published: February 2024

Cis-genetic effects are key determinants of transcriptional divergence in discrete tissues and cell types. However, how cis- and trans-effects act across continuous trajectories of cellular differentiation in vivo is poorly understood. Here, we quantify allele-specific expression during spermatogenic differentiation at single-cell resolution in an F1 hybrid mouse system, allowing for the comprehensive characterisation of cis- and trans-genetic effects, including their dynamics across cellular differentiation. Collectively, almost half of the genes subject to genetic regulation show evidence for dynamic cis-effects that vary during differentiation. Our system also allows us to robustly identify dynamic trans-effects, which are less pervasive than cis-effects. In aggregate, genetic effects were strongest in round spermatids, which parallels their increased transcriptional divergence we identified between species. Our approach provides a comprehensive quantification of the variability of genetic effects in vivo, and demonstrates a widely applicable strategy to dissect the impact of regulatory variants on gene regulation in dynamic systems.
Unified picture of vibrational relaxation of OH stretch at the air/water interface
Authors: Sung Woongmo , Inoue Ken-ichi , Nihonyanagi Satoshi , Tahara Tahei
Published: February 2024

The elucidation of the energy dissipation process is crucial for understanding various phenomena occurring in nature. Yet, the vibrational relaxation and its timescale at the water interface, where the hydrogen-bonding network is truncated, are not well understood and are still under debate. In the present study, we focus on the OH stretch of interfacial water at the air/water interface and investigate its vibrational relaxation by femtosecond time-resolved, heterodyne-detected vibrational sum-frequency generation (TR-HD-VSFG) spectroscopy. The temporal change of the vibrationally excited hydrogen-bonded (HB) OH stretch band (ν=1→2 transition) is measured, enabling us to determine reliable vibrational relaxation (T1) time. The T1 times obtained with direct excitations of HB OH stretch are 0.2-0.4 ps, which are similar to the T1 time in bulk water and do not noticeably change with the excitation frequency. It suggests that vibrational relaxation of the interfacial HB OH proceeds predominantly with the intramolecular relaxation mechanism as in the case of bulk water. The delayed rise and following decay of the excited-state HB OH band are observed with excitation of free OH stretch, indicating conversion from excited free OH to excited HB OH (~0.9 ps) followed by relaxation to low-frequency vibrations (~0.3 ps). This study provides a complete set of the T1 time of the interfacial OH stretch and presents a unified picture of its vibrational relaxation at the air/water interface.
Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage
Authors: Ruz-Maldonado Inmaculada , Gonzalez John T. , Zhang Hanming , Sun Jonathan , Bort Alicia , Kabir Inamul , Kibbey Richard G. , Suárez Yajaira , Greif Daniel M. , Fernández-Hernando Carlos
Published: February 2024

Midlobular hepatocytes are proposed to be the most plastic hepatic cell, providing a reservoir for hepatocyte proliferation during homeostasis and regeneration. However, other mechanisms beyond hyperplasia have been little explored and the contribution of other hepatocyte subpopulations to regeneration has been controversial. Thus, re-examining hepatocyte dynamics during regeneration is critical for cell therapy and treatment of liver diseases. Using a mouse model of hepatocyte- and non-hepatocyte- multicolor lineage tracing, we demonstrate that midlobular hepatocytes also undergo hypertrophy in response to chemical, physical, and viral insults. Our study shows that this subpopulation also combats liver impairment after infection with coronavirus. Furthermore, we demonstrate that pericentral hepatocytes also expand in number and size during the repair process and Galectin-9-CD44 pathway may be critical for driving these processes. Notably, we also identified that transdifferentiation and cell fusion during regeneration after severe injury contribute to recover hepatic function.
Tailoring tokamak error fields to control plasma instabilities and transport
Authors: Yang SeongMoo , Park Jong-Kyu , Jeon YoungMu , Logan Nikolas C. , Lee Jaehyun , Hu Qiming , Lee JongHa , Kim SangKyeun , Kim Jaewook , Lee Hyungho , Na Yong-Su , Hahm Taik Soo , Choi Gyungjin , Snipes Joseph A. , Park Gunyoung , Ko Won-Ha
Published: February 2024

A tokamak relies on the axisymmetric magnetic fields to confine fusion plasmas and aims to deliver sustainable and clean energy. However, misalignments arise inevitably in the tokamak construction, leading to small asymmetries in the magnetic field known as error fields (EFs). The EFs have been a major concern in the tokamak approaches because small EFs, even less than 0.1%, can drive a plasma disruption. Meanwhile, the EFs in the tokamak can be favorably used for controlling plasma instabilities, such as edge-localized modes (ELMs). Here we show an optimization that tailors the EFs to maintain an edge 3D response for ELM control with a minimized core 3D response to avoid plasma disruption and unnecessary confinement degradation. We design and demonstrate such an edge-localized 3D response in the KSTAR facility, benefiting from its unique flexibility to change many degrees of freedom in the 3D coil space for the various fusion plasma regimes. This favorable control of the tokamak EF represents a notable advance for designing intrinsically 3D tokamaks to optimize stability and confinement for next-step fusion reactors.
Robust links in photoactive covalent organic frameworks enable effective photocatalytic reactions under harsh conditions
Authors: Wang Jia-Rui , Song Kepeng , Luan Tian-Xiang , Cheng Ke , Wang Qiurong , Wang Yue , Yu William W. , Li Pei-Zhou , Zhao Yanli
Published: February 2024

Developing heterogeneous photocatalysts for the applications in harsh conditions is of high importance but challenging. Herein, by converting the imine linkages into quinoline groups of triphenylamine incorporated covalent organic frameworks (COFs), two photosensitive COFs, namely TFPA-TAPT-COF-Q and TFPA-TPB-COF-Q, are successfully constructed. The obtained quinoline-linked COFs display improved stability and photocatalytic activity, making them suitable photocatalysts for photocatalytic reactions under harsh conditions, as verified by the recyclable photocatalytic reactions of organic acid involving oxidative decarboxylation and organic base involving benzylamine coupling. Under strong oxidative condition, the quinoline-linked COFs show a high efficiency up to 11831.6 μmol·g−1·h−1 and a long-term recyclable usability for photocatalytic production of H2O2, while the pristine imine-linked COFs are less catalytically active and easily decomposed in these harsh conditions. The results demonstrate that enhancing the linkage robustness of photoactive COFs is a promising strategy to construct heterogeneous catalysts for photocatalytic reactions under harsh conditions.
Sustainable conversion of alkaline nitrate to ammonia at activities greater than 2 A cm−2
Authors: Liao Wanru , Wang Jun , Ni Ganghai , Liu Kang , Liu Changxu , Chen Shanyong , Wang Qiyou , Chen Yingkang , Luo Tao , Wang Xiqing , Wang Yanqiu , Li Wenzhang , Chan Ting-Shan , Ma Chao , Li Hongmei , Liang Ying , Liu Weizhen , Fu Junwei , Xi Beidou , Liu Min
Published: February 2024

Nitrate (NO3‒) pollution poses significant threats to water quality and global nitrogen cycles. Alkaline electrocatalytic NO3‒ reduction reaction (NO3RR) emerges as an attractive route for enabling NO3‒ removal and sustainable ammonia (NH3) synthesis. However, it suffers from insufficient proton (H+) supply in high pH conditions, restricting NO3‒-to-NH3 activity. Herein, we propose a halogen-mediated H+ feeding strategy to enhance the alkaline NO3RR performance. Our platform achieves near-100% NH3 Faradaic efficiency (pH = 14) with a current density of 2 A cm–2 and enables an over 99% NO3–-to-NH3 conversion efficiency. We also convert NO3‒ to high-purity NH4Cl with near-unity efficiency, suggesting a practical approach to valorizing pollutants into valuable ammonia products. Theoretical simulations and in situ experiments reveal that Cl-coordination endows a shifted d-band center of Pd atoms to construct local H+-abundant environments, through arousing dangling O-H water dissociation and fast *H desorption, for *NO intermediate hydrogenation and finally effective NO3‒-to-NH3 conversion.
Structural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining
Authors: Stinson Benjamin M. , Carney Sean M. , Walter Johannes C. , Loparo Joseph J.
Published: February 2024

Nonhomologous end joining (NHEJ), the primary pathway of vertebrate DNA double-strand-break (DSB) repair, directly re-ligates broken DNA ends. Damaged DSB ends that cannot be immediately re-ligated are modified by NHEJ processing enzymes, including error-prone polymerases and nucleases, to enable ligation. However, DSB ends that are initially compatible for re-ligation are typically joined without end processing. As both ligation and end processing occur in the short-range (SR) synaptic complex that closely aligns DNA ends, it remains unclear how ligation of compatible ends is prioritized over end processing. In this study, we identify structural interactions of the NHEJ-specific DNA Ligase IV (Lig4) within the SR complex that prioritize ligation and promote NHEJ fidelity. Mutational analysis demonstrates that Lig4 must bind DNA ends to form the SR complex. Furthermore, single-molecule experiments show that a single Lig4 binds both DNA ends at the instant of SR synapsis. Thus, Lig4 is poised to ligate compatible ends upon initial formation of the SR complex before error-prone processing. Our results provide a molecular basis for the fidelity of NHEJ.
Intercellular transfer of cancer cell invasiveness via endosome-mediated protease shedding
Authors: Wenzel Eva Maria , Pedersen Nina Marie , Elfmark Liv Anker , Wang Ling , Kjos Ingrid , Stang Espen , Malerød Lene , Brech Andreas , Stenmark Harald , Raiborg Camilla
Published: February 2024

Overexpression of the transmembrane matrix metalloproteinase MT1-MMP/MMP14 promotes cancer cell invasion. Here we show that MT1-MMP-positive cancer cells turn MT1-MMP-negative cells invasive by transferring a soluble catalytic ectodomain of MT1-MMP. Surprisingly, this effect depends on the presence of TKS4 and TKS5 in the donor cell, adaptor proteins previously implicated in invadopodia formation. In endosomes of the donor cell, TKS4/5 promote ADAM-mediated cleavage of MT1-MMP by bridging the two proteases, and cleavage is stimulated by the low intraluminal pH of endosomes. The bridging depends on the PX domains of TKS4/5, which coincidently interact with the cytosolic tail of MT1-MMP and endosomal phosphatidylinositol 3-phosphate. MT1-MMP recruits TKS4/5 into multivesicular endosomes for their subsequent co-secretion in extracellular vesicles, together with the enzymatically active ectodomain. The shed ectodomain converts non-invasive recipient cells into an invasive phenotype. Thus, TKS4/5 promote intercellular transfer of cancer cell invasiveness by facilitating ADAM-mediated shedding of MT1-MMP in acidic endosomes.
Regression-based Deep-Learning predicts molecular biomarkers from pathology slides
Authors: El Nahhas Omar S. M. , Loeffler Chiara M. L. , Carrero Zunamys I. , van Treeck Marko , Kolbinger Fiona R. , Hewitt Katherine J. , Muti Hannah S. , Graziani Mara , Zeng Qinghe , Calderaro Julien , Ortiz-Brüchle Nadina , Yuan Tanwei , Hoffmeister Michael , Brenner Hermann , Brobeil Alexander , Reis-Filho Jorge S. , Kather Jakob Nikolas
Published: February 2024

Deep Learning (DL) can predict biomarkers from cancer histopathology. Several clinically approved applications use this technology. Most approaches, however, predict categorical labels, whereas biomarkers are often continuous measurements. We hypothesize that regression-based DL outperforms classification-based DL. Therefore, we develop and evaluate a self-supervised attention-based weakly supervised regression method that predicts continuous biomarkers directly from 11,671 images of patients across nine cancer types. We test our method for multiple clinically and biologically relevant biomarkers: homologous recombination deficiency score, a clinically used pan-cancer biomarker, as well as markers of key biological processes in the tumor microenvironment. Using regression significantly enhances the accuracy of biomarker prediction, while also improving the predictions’ correspondence to regions of known clinical relevance over classification. In a large cohort of colorectal cancer patients, regression-based prediction scores provide a higher prognostic value than classification-based scores. Our open-source regression approach offers a promising alternative for continuous biomarker analysis in computational pathology.
Diffusive kinks turn kirigami into machines
Authors: Janbaz Shahram , Coulais Corentin
Published: February 2024

Kinks define boundaries between distinct configurations of a material. In the context of mechanical metamaterials, kinks have recently been shown to underpin logic, shape-changing and locomotion functionalities. So far such kinks propagate by virtue of inertia or of an external load. Here, we discover the emergence of propagating kinks in purely dissipative kirigami. To this end, we create kirigami that shape-change into different textures depending on how fast they are stretched. We find that if we stretch fast and wait, the viscoelastic kirigami can eventually snap from one texture to another. Crucially, such a snapping instability occurs in a sequence and a propagating diffusive kink emerges. As such, it mimics the slow sequential folding observed in biological systems, e.g., Mimosa Pudica. We finally demonstrate that diffusive kinks can be harnessed for basic machine-like functionalities, such as sensing, dynamic shape morphing, transport and manipulation of objects.
Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control
Authors: Ng Annabel Qi En , Chan Seow Neng , Pek Jun Wei
Published: February 2024

Mitochondria are inherited exclusively from the mothers and are required for the proper development of embryos. Hence, germline mitochondrial quality is highly regulated during oogenesis to ensure oocyte viability. How nutrient availability influences germline mitochondrial quality control is unclear. Here we find that fasting leads to the accumulation of mitochondrial clumps and oogenesis arrest inDrosophila. Fasting induces the downregulation of the DIP1-Clueless pathway, leading to an increase in the expression of a stable intronic sequence RNA calledsisR-1. Mechanistically,sisR-1localizes to the mitochondrial clumps to inhibit the poly-ubiquitination of the outer mitochondrial protein Porin/VDAC1, thereby suppressing p62-mediated mitophagy. Alleviation of the fasting-induced highsisR-1levels by eithersisR-1RNAi or refeeding leads to mitophagy, the resumption of oogenesis and an improvement in oocyte quality. Thus, our study provides a possible mechanism by which fasting can improve oocyte quality by modulating the mitochondrial quality control pathway. Of note, we uncover that thesisR-1response also regulates mitochondrial clumping and oogenesis during protein deprivation, heat shock and aging, suggesting a broader role for this mechanism in germline mitochondrial quality control.
Pick-up single-cell proteomic analysis for quantifying up to 3000 proteins in a Mammalian cell
Authors: Wang Yu , Guan Zhi-Ying , Shi Shao-Wen , Jiang Yi-Rong , Zhang Jie , Yang Yi , Wu Qiong , Wu Jie , Chen Jian-Bo , Ying Wei-Xin , Xu Qin-Qin , Fan Qian-Xi , Wang Hui-Feng , Zhou Li , Wang Ling , Fang Jin , Pan Jian-Zhang , Fang Qun
Published: February 2024

The shotgun proteomic analysis is currently the most promising single-cell protein sequencing technology, however its identification level of ~1000 proteins per cell is still insufficient for practical applications. Here, we develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep identification capable of quantifying up to 3000 protein groups in a mammalian cell using the label-free quantitative method. The PiSPA workflow is specially established for single-cell samples mainly based on a nanoliter-scale microfluidic liquid handling robot, capable of achieving single-cell capture, pretreatment and injection under the pick-up operation strategy. Using this customized workflow with remarkable improvement in protein identification, 2449–3500, 2278–3257 and 1621–2904 protein groups are quantified in single A549 cells (n = 37), HeLa cells (n = 44) and U2OS cells (n = 27) under the DIA (MBR) mode, respectively. Benefiting from the flexible cell picking-up ability, we study HeLa cell migration at the single cell proteome level, demonstrating the potential in practical biological research from single-cell insight.
Eco-evolutionary dynamics of gut phageome in wild gibbons (Hoolock tianxing) with seasonal diet variations
Authors: Gao Shao-Ming , Fei Han-Lan , Li Qi , Lan Li-Ying , Huang Li-Nan , Fan Peng-Fei
Published: February 2024

It has been extensively studied that the gut microbiome provides animals flexibility to adapt to food variability. Yet, how gut phageome responds to diet variation of wild animals remains unexplored. Here, we analyze the eco-evolutionary dynamics of gut phageome in six wild gibbons (Hoolock tianxing) by collecting individually-resolved fresh fecal samples and parallel feeding behavior data for 15 consecutive months. Application of complementary viral and microbial metagenomics recovers 39,198 virulent and temperate phage genomes from the feces. Hierarchical cluster analyses show remarkable seasonal diet variations in gibbons. From high-fruit to high-leaf feeding period, the abundances of phage populations are seasonally fluctuated, especially driven by the increased abundance of virulent phages that kill the Lachnospiraceae hosts, and a decreased abundance of temperate phages that piggyback the Bacteroidaceae hosts. Functional profiling reveals an enrichment through horizontal gene transfers of toxin-antitoxin genes on temperate phage genomes in high-leaf season, potentially conferring benefits to their prokaryotic hosts. The phage-host ecological dynamics are driven by the coevolutionary processes which select for tail fiber and DNA primase genes on virulent and temperate phage genomes, respectively. Our results highlight complex phageome-microbiome interactions as a key feature of the gibbon gut microbial ecosystem responding to the seasonal diet.
High intrinsic phase stability of ultrathin 2M WS2
Authors: Liu Xiangye , Zhang Pingting , Wang Shiyao , Fang Yuqiang , Wu Penghui , Xiang Yue , Chen Jipeng , Zhao Chendong , Zhang Xian , Zhao Wei , Wang Junjie , Huang Fuqiang , Guan Cao
Published: February 2024

Metallic 2M or 1T′-phase transition metal dichalcogenides (TMDs) attract increasing interests owing to their fascinating physicochemical properties, such as superconductivity, optical nonlinearity, and enhanced electrochemical activity. However, these TMDs are metastable and tend to transform to the thermodynamically stable 2H phase. In this study, through systematic investigation and theoretical simulation of phase change of 2M WS2, we demonstrate that ultrathin 2M WS2 has significantly higher intrinsic thermal stabilities than the bulk counterparts. The 2M-to-2H phase transition temperature increases from 120 °C to 210 °C in the air as thickness of WS2 is reduced from bulk to bilayer. Monolayered 1T′ WS2 can withstand temperatures up to 350 °C in the air before being oxidized, and up to 450 °C in argon atmosphere before transforming to 1H phase. The higher stability of thinner 2M WS2 is attributed to stiffened intralayer bonds, enhanced thermal conductivity and higher average barrier per layer during the layer(s)-by-layer(s) phase transition process. The observed high intrinsic phase stability can expand the practical applications of ultrathin 2M TMDs.
Twofold rigidity activates ultralong organic high-temperature phosphorescence
Authors: Chen Kaijun , Zhang Yongfeng , Lei Yunxiang , Dai Wenbo , Liu Miaochang , Cai Zhengxu , Wu Huayue , Huang Xiaobo , Ma Xiang
Published: February 2024

A strategy is pioneered for achieving high-temperature phosphorescence using planar rigid molecules as guests and rigid polymers as host matrix. The planar rigid configuration can resist the thermal vibration of the guest at high temperatures, and the rigidity of the matrix further enhances the high-temperature resistance of the guest. The doped materials exhibit an afterglow of 40 s at 293 K, 20 s at 373 K, 6 s at 413 K, and a 1 s afterglow at 433 K. The experimental results indicate that as the rotational ability of the groups connected to the guests gradually increases, the high-temperature phosphorescence performance of the doped materials gradually decreases. In addition, utilizing the property of doped materials that can emit phosphorescence at high temperatures and in high smoke, the attempt is made to use organic phosphorescence materials to identify rescue workers and trapped personnel in fires.