bluuebunny/crossref_metadata_2025_split huggingface dataset:
The redox language in neurodegenerative diseases: oxidative post-translational modifications by hydrogen peroxide
Authors: Lee Yew Mun , He Weifeng , Liou Yih-Cherng 
Published: January 2021

AbstractNeurodegenerative diseases, a subset of age-driven diseases, have been known to exhibit increased oxidative stress. The resultant increase in reactive oxygen species (ROS) has long been viewed as a detrimental byproduct of many cellular processes. Despite this, therapeutic approaches using antioxidants were deemed unsuccessful in circumventing neurodegenerative diseases. In recent times, it is widely accepted that these toxic by-products could act as secondary messengers, such as hydrogen peroxide (H2O2), to drive important signaling pathways. Notably, mitochondria are considered one of the major producers of ROS, especially in the production of mitochondrial H2O2. As a secondary messenger, cellular H2O2can initiate redox signaling through oxidative post-translational modifications (oxPTMs) on the thiol group of the amino acid cysteine. With the current consensus that cellular ROS could drive important biological signaling pathways through redox signaling, researchers have started to investigate the role of cellular ROS in the pathogenesis of neurodegenerative diseases. Moreover, mitochondrial dysfunction has been linked to various neurodegenerative diseases, and recent studies have started to focus on the implications of mitochondrial ROS from dysfunctional mitochondria on the dysregulation of redox signaling. Henceforth, in this review, we will focus our attention on the redox signaling of mitochondrial ROS, particularly on mitochondrial H2O2, and its potential implications with neurodegenerative diseases.
Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI
Authors: Chen Chuan’ai , Wang Dekun , Yu Yangyang , Zhao Tianyuan , Min Ningning , Wu Yan , Kang Lichun , Zhao Yong , Du Lingfang , Zhang Mianzhi , Gong Junbo , Zhang Zhujun , Zhang Yuying , Mi Xue , Yue Shijing , Tan Xiaoyue 
Published: January 2021

AbstractLegumain is required for maintenance of normal kidney homeostasis. However, its role in acute kidney injury (AKI) is still unclear. Here, we induced AKI by bilateral ischemia-reperfusion injury (IRI) of renal arteries or folic acid in lgmnWT and lgmnKO mice. We assessed serum creatinine, blood urea nitrogen, histological indexes of tubular injury, and expression of KIM-1 and NGAL. Inflammatory infiltration was evaluated by immunohistological staining of CD3 and F4/80, and expression of TNF-α, CCL-2, IL-33, and IL-1α. Ferroptosis was evaluated by Acsl4, Cox-2, reactive oxygen species (ROS) indexes H2DCFDA and DHE, MDA and glutathione peroxidase 4 (GPX4). We induced ferroptosis by hypoxia or erastin in primary mouse renal tubular epithelial cells (mRTECs). Cellular survival, Acsl4, Cox-2, LDH release, ROS, and MDA levels were measured. We analyzed the degradation of GPX4 through inhibition of proteasomes or autophagy. Lysosomal GPX4 was assessed to determine GPX4 degradation pathway. Immunoprecipitation (IP) was used to determine the interactions between legumain, GPX4, HSC70, and HSP90. For tentative treatment, RR-11a was administrated intraperitoneally to a mouse model of IRI-induced AKI. Our results showed that legumain deficiency attenuated acute tubular injury, inflammation, and ferroptosis in either IRI or folic acid-induced AKI model. Ferroptosis induced by hypoxia or erastin was dampened in lgmnKO mRTECs compared with lgmnWT control. Deficiency of legumain prevented chaperone-mediated autophagy of GPX4. Results of IP suggested interactions between legumain, HSC70, HSP90, and GPX4. Administration of RR-11a ameliorated ferroptosis and renal injury in the AKI model. Together, our data indicate that legumain promotes chaperone-mediated autophagy of GPX4 therefore facilitates tubular ferroptosis in AKI.
Galectin-1 accelerates high-fat diet-induced obesity by activation of peroxisome proliferator-activated receptor gamma (PPARγ) in mice
Authors: Baek Jung-Hwan , Kim Da-Hyun , Lee Jaegyeong , Kim Seok-Jun , Chun Kyung-Hee 
Published: January 2021

AbstractGalectin-1 contains a carbohydrate-recognition domain (CRD) as a member of the lectin family. Here, we investigated whether galectin-1 regulates adipogenesis and lipid accumulation. Galectin-1 mRNA is highly expressed in metabolic tissues such as the muscle and adipose tissues. Higher mRNA expression of galectin-1 was detected in white adipose tissues (WATs) of mice that were fed a high-fat diet (HFD) than in those of mice fed a normal-fat diet (NFD). Protein expression of galectin-1 also increased during adipocyte differentiation. Galectin-1 silencing inhibited the differentiation of 3T3-L1 cells and the expression of lipogenic factors, such as PPARγ, C/EBPα, FABP4, and FASN at both mRNA and protein levels. Lactose, an inhibitor by the binding with CRD of galectin-1 in extracellular matrix, did not affect adipocyte differentiation. Galectin-1 is localized in multiple cellular compartments in 3T3-L1 cells. However, we found that DMI (dexamethasone, methylisobutylxanthine, insulin) treatment increased its nuclear localization. Interestingly, galectin-1 interacted with PPARγ. Galectin-1 overexpression resulted in increased PPARγ expression and transcriptional activity. Furthermore, we prepared galectin-1-knockout (Lgals1−/−) mice and fed a 60% HFD. After 10 weeks, Lgals1−/− mice exhibited lower body weight and gonadal WAT (gWAT) mass than wild-type mice. Fasting glucose level was also lower in Lgals1−/−mice than that in wild-type mice. Moreover, lipogenic genes were significantly downregulated in the gWATs and liver tissues from Lgals1−/− mice. Pro-inflammatory cytokines, such as CCL2, CCL3, TNFα, and F4/80, as well as macrophage markers, were also drastically downregulated in the gWATs and liver tissues of Lgals1−/− mice. In addition, Lgals1−/−mice showed elevated expression of genes involved in thermogenesis in the brown adipose tissue. Collectively, galectin-1 exacerbates obesity of mice fed HFD by increment of PPARγ expression and activation. Our findings suggest that galectin-1 could be a potential therapeutic target for obesity and needed further study for clinical application.
Taurocholic acid inhibits the response to interferon-α therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function
Authors: Xun Zhen , Lin Jinpiao , Yu Qingqing , Liu Can , Huang Jinlan , Shang Hongyan , Guo Jianhui , Ye Yuchen , Wu Wennan , Zeng Yongbin , Wu Songhang , Xu Siyi , Chen Tianbin , Chen Jing , Ou Qishui 
Published: January 2021

AbstractPegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3+CD8+ T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3+CD8+ T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3+CD8+ T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment.
Clinical validation of an artificial intelligence-based diabetic retinopathy screening tool for a national health system
Authors: Arenas-Cavalli José Tomás , Abarca Ignacio , Rojas-Contreras Maximiliano , Bernuy Fernando , Donoso Rodrigo 
Published: January 2021

Abstract
Objective
To evaluate the accuracy and validity of an automated diabetic retinopathy (DR) screening tool (DART, TeleDx, Santiago, Chile) that uses artificial intelligence to analyze ocular fundus photographs for potential implementation in the national Chilean DR screening programme.

Method
This was an observational study of 1123 diabetic eye exams using a validation protocol designed by the commission of the Chilean Ministry of Health personnel and retina specialists.

Results
Receiver operating characteristic (ROC) analysis indicated a sensitivity of 94.6% (95% CI: 90.9–96.9%), specificity of 74.3% (95% CI: 73.3–75%), and negative predictive value of 98.1% (95% CI: 96.8–98.9%) for the automated tool at the optimal operating point for DR screening. The area under the ROC curve was 0.915.

Conclusions
The results of this study suggest that DART is a valid tool that could be implemented in a heterogeneous health network such as the Chilean system.
Synthesis of molecular metallic barium superhydride: pseudocubic BaH12
Authors: Chen Wuhao , Semenok Dmitrii V. , Kvashnin Alexander G. , Huang Xiaoli , Kruglov Ivan A. , Galasso Michele , Song Hao , Duan Defang , Goncharov Alexander F. , Prakapenka Vitali B. , Oganov Artem R. , Cui Tian 
Published: January 2021

AbstractFollowing the discovery of high-temperature superconductivity in the La–H system, we studied the formation of new chemical compounds in the barium-hydrogen system at pressures from 75 to 173 GPa. Using in situ generation of hydrogen from NH3BH3, we synthesized previously unknown superhydride BaH12 with a pseudocubic (fcc) Ba sublattice in four independent experiments. Density functional theory calculations indicate close agreement between the theoretical and experimental equations of state. In addition, we identified previously known P6/mmm-BaH2 and possibly BaH10 and BaH6 as impurities in the samples. Ab initio calculations show that newly discovered semimetallic BaH12 contains H2 and H3– molecular units and detached H12 chains which are formed as a result of a Peierls-type distortion of the cubic cage structure. Barium dodecahydride is a unique molecular hydride with metallic conductivity that demonstrates the superconducting transition around 20 K at 140 GPa.
Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference
Authors: Takayama Jun , Tadaka Shu , Yano Kenji , Katsuoka Fumiki , Gocho Chinatsu , Funayama Takamitsu , Makino Satoshi , Okamura Yasunobu , Kikuchi Atsuo , Sugimoto Sachiyo , Kawashima Junko , Otsuki Akihito , Sakurai-Yageta Mika , Yasuda Jun , Kure Shigeo , Kinoshita Kengo , Yamamoto Masayuki , Tamiya Gen 
Published: January 2021

AbstractThe complete human genome sequence is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the reference genome (e.g., GRCh37) due to its bias toward European and African ancestries. Here, we perform de novo assembly of three Japanese male genomes using > 100× Pacific Biosciences long reads and Bionano Genomics optical maps per sample. We integrate the genomes using the major allele for consensus and anchor the scaffolds using genetic and radiation hybrid maps to reconstruct each chromosome. The resulting genome sequence, JG1, is contiguous, accurate, and carries the Japanese major allele at most loci. We adopt JG1 as the reference for confirmatory exome re-analyses of seven rare-disease Japanese families and find that re-analysis using JG1 reduces total candidate variant calls versus GRCh37 while retaining disease-causing variants. These results suggest that integrating multiple genomes from a single population can aid genome analyses of that population.
Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma
Authors: Nguyen Phuong H. D. , Ma Siming , Phua Cheryl Z. J. , Kaya Neslihan A. , Lai Hannah L. H. , Lim Chun Jye , Lim Jia Qi , Wasser Martin , Lai Liyun , Tam Wai Leong , Lim Tony K. H. , Wan Wei Keat , Loh Tracy , Leow Wei Qiang , Pang Yin Huei , Chan Chung Yip , Lee Ser Yee , Cheow Peng Chung , Toh Han Chong , Ginhoux Florent , Iyer Shridhar , Kow Alfred W. C. , Young Dan Yock , Chung Alexander , Bonney Glen K. , Goh Brian K. P. , Albani Salvatore , Chow Pierce K. H. , Zhai Weiwei , Chew Valerie 
Published: January 2021

AbstractThe clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.
Dynamics of soliton self-injection locking in optical microresonators
Authors: Voloshin Andrey S. , Kondratiev Nikita M. , Lihachev Grigory V. , Liu Junqiu , Lobanov Valery E. , Dmitriev Nikita Yu. , Weng Wenle , Kippenberg Tobias J. , Bilenko Igor A. 
Published: January 2021

AbstractSoliton microcombs constitute chip-scale optical frequency combs, and have the potential to impact a myriad of applications from frequency synthesis and telecommunications to astronomy. The demonstration of soliton formation via self-injection locking of the pump laser to the microresonator has significantly relaxed the requirement on the external driving lasers. Yet to date, the nonlinear dynamics of this process has not been fully understood. Here, we develop an original theoretical model of the laser self-injection locking to a nonlinear microresonator, i.e., nonlinear self-injection locking, and construct state-of-the-art hybrid integrated soliton microcombs with electronically detectable repetition rate of 30 GHz and 35 GHz, consisting of a DFB laser butt-coupled to a silicon nitride microresonator chip. We reveal that the microresonator’s Kerr nonlinearity significantly modifies the laser diode behavior and the locking dynamics, forcing laser emission frequency to be red-detuned. A novel technique to study the soliton formation dynamics as well as the repetition rate evolution in real-time uncover non-trivial features of the soliton self-injection locking, including soliton generation at both directions of the diode current sweep. Our findings provide the guidelines to build electrically driven integrated microcomb devices that employ full control of the rich dynamics of laser self-injection locking, key for future deployment of microcombs for system applications.
Anti-senescent drug screening by deep learning-based morphology senescence scoring
Authors: Kusumoto Dai , Seki Tomohisa , Sawada Hiromune , Kunitomi Akira , Katsuki Toshiomi , Kimura Mai , Ito Shogo , Komuro Jin , Hashimoto Hisayuki , Fukuda Keiichi , Yuasa Shinsuke 
Published: January 2021

AbstractAdvances in deep learning technology have enabled complex task solutions. The accuracy of image classification tasks has improved owing to the establishment of convolutional neural networks (CNN). Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Furthermore, it is a potential therapeutic target. Specific molecular markers are used to identify senescent cells. Moreover senescent cells show unique morphology, which can be identified. We develop a successful morphology-based CNN system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells by senescence probability output from pre-trained CNN optimised for the classification of cellular senescence, Deep Learning-Based Senescence Scoring System by Morphology (Deep-SeSMo). Deep-SeSMo correctly evaluates the effects of well-known anti-senescent reagents. We screen for drugs that control cellular senescence using a kinase inhibitor library by Deep-SeSMo-based drug screening and identify four anti-senescent drugs. RNA sequence analysis reveals that these compounds commonly suppress senescent phenotypes through inhibition of the inflammatory response pathway. Thus, morphology-based CNN system can be a powerful tool for anti-senescent drug screening.
Efficient carbon dioxide hydrogenation to formic acid with buffering ionic liquids
Authors: Weilhard Andreas , Argent Stephen P. , Sans Victor 
Published: January 2021

AbstractThe efficient transformation of CO2 into chemicals and fuels is a key challenge for the decarbonisation of the synthetic production chain. Formic acid (FA) represents the first product of CO2 hydrogenation and can be a precursor of higher added value products or employed as a hydrogen storage vector. Bases are typically required to overcome thermodynamic barriers in the synthesis of FA, generating waste and requiring post-processing of the formate salts. The employment of buffers can overcome these limitations, but their catalytic performance has so far been modest. Here, we present a methodology utilising IL as buffers to catalytically transform CO2 into FA with very high efficiency and comparable performance to the base-assisted systems. The combination of multifunctional basic ionic liquids and catalyst design enables the synthesis of FA with very high catalytic efficiency in TONs of >8*105 and TOFs > 2.1*104 h−1.
How ice grows from premelting films and water droplets
Authors: Sibley David N. , Llombart Pablo , Noya Eva G. , Archer Andrew J. , MacDowell Luis G. 
Published: January 2021

AbstractClose to the triple point, the surface of ice is covered by a thin liquid layer (so-called quasi-liquid layer) which crucially impacts growth and melting rates. Experimental probes cannot observe the growth processes below this layer, and classical models of growth by vapor deposition do not account for the formation of premelting films. Here, we develop a mesoscopic model of liquid-film mediated ice growth, and identify the various resulting growth regimes. At low saturation, freezing proceeds by terrace spreading, but the motion of the buried solid is conveyed through the liquid to the outer liquid–vapor interface. At higher saturations water droplets condense, a large crater forms below, and freezing proceeds undetectably beneath the droplet. Our approach is a general framework that naturally models freezing close to three phase coexistence and provides a first principle theory of ice growth and melting which may prove useful in the geosciences.
Stabilizing the closed SARS-CoV-2 spike trimer
Authors: Juraszek Jarek , Rutten Lucy , Blokland Sven , Bouchier Pascale , Voorzaat Richard , Ritschel Tina , Bakkers Mark J. G. , Renault Ludovic L. R. , Langedijk Johannes P. M. 
Published: January 2021

AbstractThe trimeric spike (S) protein of SARS-CoV-2 is the primary focus of most vaccine design and development efforts. Due to intrinsic instability typical of class I fusion proteins, S tends to prematurely refold to the post-fusion conformation, compromising immunogenic properties and prefusion trimer yields. To support ongoing vaccine development efforts, we report the structure-based design of soluble S trimers with increased yields and stabilities, based on introduction of single point mutations and disulfide-bridges. We identify regions critical for stability: the heptad repeat region 1, the SD1 domain and position 614 in SD2. We combine a minimal selection of mostly interprotomeric mutations to create a stable S-closed variant with a 6.4-fold higher expression than the parental construct while no longer containing a heterologous trimerization domain. The cryo-EM structure reveals a correctly folded, predominantly closed pre-fusion conformation. Highly stable and well producing S protein and the increased understanding of S protein structure will support vaccine development and serological diagnostics.
Alternating quarantine for sustainable epidemic mitigation
Authors: Meidan Dror , Schulmann Nava , Cohen Reuven , Haber Simcha , Yaniv Eyal , Sarid Ronit , Barzel Baruch 
Published: January 2021

AbstractAbsent pharmaceutical interventions, social distancing, lock-downs and mobility restrictions remain our prime response in the face of epidemic outbreaks. To ease their potentially devastating socioeconomic consequences, we propose here an alternating quarantine strategy: at every instance, half of the population remains under lockdown while the other half continues to be active - maintaining a routine of weekly succession between activity and quarantine. This regime minimizes infectious interactions, as it allows only half of the population to interact for just half of the time. As a result it provides a dramatic reduction in transmission, comparable to that achieved by a population-wide lockdown, despite sustaining socioeconomic continuity at ~50% capacity. The weekly alternations also help address the specific challenge of COVID-19, as their periodicity synchronizes with the natural SARS-CoV-2 disease time-scales, allowing to effectively isolate the majority of infected individuals precisely at the time of their peak infection.
Bidirectional contact tracing could dramatically improve COVID-19 control
Authors: Bradshaw William J. , Alley Ethan C. , Huggins Jonathan H. , Lloyd Alun L. , Esvelt Kevin M. 
Published: January 2021

AbstractContact tracing is critical to controlling COVID-19, but most protocols only “forward-trace” to notify people who were recently exposed. Using a stochastic branching-process model, we find that “bidirectional” tracing to identify infector individuals and their other infectees robustly improves outbreak control. In our model, bidirectional tracing more than doubles the reduction in effective reproduction number (Reff) achieved by forward-tracing alone, while dramatically increasing resilience to low case ascertainment and test sensitivity. The greatest gains are realised by expanding the manual tracing window from 2 to 6 days pre-symptom-onset or, alternatively, by implementing high-uptake smartphone-based exposure notification; however, to achieve the performance of the former approach, the latter requires nearly all smartphones to detect exposure events. With or without exposure notification, our results suggest that implementing bidirectional tracing could dramatically improve COVID-19 control.