bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting p53 pathways: mechanisms, structures and advances in therapy
Authors: Wang Haolan , Guo Ming , Wei Hudie , Chen Yongheng 
Published: March 2023

AbstractThe TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the “guardian of the genome”. Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an “undruggable” target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.
MESP2 binds competitively to TCF4 to suppress gastric cancer progression by regulating the SKP2/p27 axis
Authors: Ge Lingjun , Zhao Gaichao , Lan Chao , Song Houji , Qi Dan , Huang Pan , Ke Xiaoxue , Cui Hongjuan 
Published: March 2023

AbstractGastric cancer (GC) is a major cause of human deaths worldwide, and is notorious for its high incidence and mortality rates. Mesoderm Posterior Basic Helix-loop-helix (bHLH) transcription factor 2 (MESP2) acts as a transcription factor with a conserved bHLH domain. However, whether MESP2 contributes to tumorigenesis and its potential molecular mechanisms, remain unexplored. Noticeably, MESP2 expression levels are decreased in GC tissues and cell lines compared to those in normal tissue. Further, in vitro and in vivo experiments have confirmed that MESP2 overexpression suppresses GC cell growth, migration, and invasion, whereas MESP2 knockdown results in the exact opposite. Here, we present the first report that MESP2 binds to transcription factor 7-like 2 (TCF7L2/TCF4) to inhibit the activation of the TCF4/beta-catenin transcriptional complex, decrease the occupancy of the complex on the S-phase kinase Associated Protein 2 (SKP2) promoter, and promote p27 accumulation. MESP2 knockdown facilitated tumorigenesis, which was partially suppressed by SKP2 knockdown. Taken together, we conclude that MESP2 binds competitively to TCF4 to suppress GC progression by regulating the SKP2/p27 axis, thus offering a potential therapeutic strategy for future treatment.
Singlet fission as a polarized spin generator for dynamic nuclear polarization
Authors: Kawashima Yusuke , Hamachi Tomoyuki , Yamauchi Akio , Nishimura Koki , Nakashima Yuma , Fujiwara Saiya , Kimizuka Nobuo , Ryu Tomohiro , Tamura Tetsu , Saigo Masaki , Onda Ken , Sato Shunsuke , Kobori Yasuhiro , Tateishi Kenichiro , Uesaka Tomohiro , Watanabe Go , Miyata Kiyoshi , Yanai Nobuhiro 
Published: March 2023

AbstractSinglet fission (SF), converting a singlet excited state into a spin-correlated triplet-pair state, is an effective way to generate a spin quintet state in organic materials. Although its application to photovoltaics as an exciton multiplier has been extensively studied, the use of its unique spin degree of freedom has been largely unexplored. Here, we demonstrate that the spin polarization of the quintet multiexcitons generated by SF improves the sensitivity of magnetic resonance of water molecules through dynamic nuclear polarization (DNP). We form supramolecular assemblies of a few pentacene chromophores and use SF-born quintet spins to achieve DNP of water-glycerol, the most basic biological matrix, as evidenced by the dependence of nuclear polarization enhancement on magnetic field and microwave power. Our demonstration opens a use of SF as a polarized spin generator in bio-quantum technology.
Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps
Authors: Muenks Andrew , Zepeda Samantha , Zhou Guangfeng , Veesler David , DiMaio Frank 
Published: March 2023

AbstractAdvances in cryo-electron microscopy (cryoEM) and deep-learning guided protein structure prediction have expedited structural studies of protein complexes. However, methods for accurately determining ligand conformations are lacking. In this manuscript, we develop EMERALD, a tool for automatically determining ligand structures guided by medium-resolution cryoEM density. We show this method is robust at predicting ligands along with surrounding side chains in maps as low as 4.5 Å local resolution. Combining this with a measure of placement confidence and running on all protein/ligand structures in the EMDB, we show that 57% of ligands replicate the deposited model, 16% confidently find alternate conformations, 22% have ambiguous density where multiple conformations might be present, and 5% are incorrectly placed. For five cases where our approach finds an alternate conformation with high confidence, high-resolution crystal structures validate our placement. EMERALD and the resulting analysis should prove critical in using cryoEM to solve protein-ligand complexes.
Defects in placental syncytiotrophoblast cells are a common cause of developmental heart disease
Authors: Radford Bethany N. , Zhao Xiang , Glazer Tali , Eaton Malcolm , Blackwell Danielle , Mohammad Shuhiba , Lo Vercio Lucas Daniel , Devine Jay , Shalom-Barak Tali , Hallgrimsson Benedikt , Cross James C. , Sucov Henry M. , Barak Yaacov , Dean Wendy , Hemberger Myriam 
Published: March 2023

AbstractPlacental abnormalities have been sporadically implicated as a source of developmental heart defects. Yet it remains unknown how often the placenta is at the root of congenital heart defects (CHDs), and what the cellular mechanisms are that underpin this connection. Here, we selected three mouse mutant lines, Atp11a, Smg9 and Ssr2, that presented with placental and heart defects in a recent phenotyping screen, resulting in embryonic lethality. To dissect phenotype causality, we generated embryo- and trophoblast-specific conditional knockouts for each of these lines. This was facilitated by the establishment of a new transgenic mouse, Sox2-Flp, that enables the efficient generation of trophoblast-specific conditional knockouts. We demonstrate a strictly trophoblast-driven cause of the CHD and embryonic lethality in one of the three lines (Atp11a) and a significant contribution of the placenta to the embryonic phenotypes in another line (Smg9). Importantly, our data reveal defects in the maternal blood-facing syncytiotrophoblast layer as a shared pathology in placentally induced CHD models. This study highlights the placenta as a significant source of developmental heart disorders, insights that will transform our understanding of the vast number of unexplained congenital heart defects.
Soil moisture-evaporation coupling shifts into new gears under increasing CO2
Authors: Hsu Hsin , Dirmeyer Paul A. 
Published: March 2023

AbstractWhen soil moisture (SM) content falls within a transitional regime between dry and wet conditions, it controls evaporation, affecting atmospheric heat and humidity. Accordingly, different SM regimes correspond to different gears of land-atmosphere coupling, affecting climate. Determining patterns of SM regimes and their future evolution is imperative. Here, we examine global SM regime distributions from ten climate models. Under increasing CO2, the range of SM extends into unprecedented coupling regimes in many locations. Solely wet regime areas decline globally by 15.9%, while transitional regimes emerge in currently humid areas of the tropics and high latitudes. Many semiarid regions spend more days in the transitional regime and fewer in the dry regime. These imply that a larger fraction of the world will evolve to experience multiple gears of land-atmosphere coupling, with the strongly coupled transitional regime expanding the most. This could amplify future climate sensitivity to land-atmosphere feedbacks and land management.
Sequence terminus dependent PCR for site-specific mutation and modification detection
Authors: Xu Gaolian , Yang Hao , Qiu Jiani , Reboud Julien , Zhen Linqing , Ren Wei , Xu Hong , Cooper Jonathan M. , Gu Hongchen 
Published: March 2023

AbstractThe detection of changes in nucleic acid sequences at specific sites remains a critical challenge in epigenetics, diagnostics and therapeutics. To date, such assays often require extensive time, expertise and infrastructure for their implementation, limiting their application in clinical settings. Here we demonstrate a generalizable method, named Specific Terminal Mediated Polymerase Chain Reaction (STEM-PCR) for the detection of DNA modifications at specific sites, in a similar way as DNA sequencing techniques, but using simple and widely accessible PCR-based workflows. We apply the technique to both for site-specific methylation and co-methylation analysis, importantly using a bisulfite-free process - so providing an ease of sample processing coupled with a sensitivity 20-fold better than current gold-standard techniques. To demonstrate the clinical applicability through the detection of single base mutations with high sensitivity and no-cross reaction with the wild-type background, we show the bisulfite-free detection of SEPTIN9 and SFRP2 gene methylation in patients (as key biomarkers in the prognosis and diagnosis of tumours).
Damage analysis and mechanism study of sol–gel coating over KDP crystal under multi-pulse of laser irradiation at low flux
Authors: You Teng-Hui , Yang Wei , Hui Hao-Hao , Lei Xiang-Yang , Wang Tian-Yu , Zhang Qing-Hua , Ju Xin , Deng Xue-Ran 
Published: March 2023

AbstractThe purpose of this study is to analyze the damage of antireflective (AR) coating over potassium dihydrogen phosphate (KDP) crystal subjected to multi-pulse laser irradiation at low flux under vacuum. Fresh silica AR was characterized as a reference; Atomic Force Microscope (AFM), Scanning Electron Microscopy (SEM), profilometer, and Scanning Near-Field Optical Microscope Photo-induced Force Microscope (SNOM-PiFM) were employed to analyze the characteristics of coatings. The experimental results indicated that the damage of AR coating over the KDP crystal was mainly caused by partial exfoliation, which exposed silica particles beneath the surface. It was found that the accumulated tensile stress led to coating damage with the increase of laser pulse. The initial coating damage was observed to extend and interconnect to form large-area exfoliation. Splitting mechanism of SiO–Si TO3 was observed at vibration mode peaks of 1064 cm−1 and 1096 cm−1showing progressing irradiation damage. Based on this study, it would be helpful to suppress the damage probability of AR coating over KDP crystal applied in high-power laser systems. Moreover, the applicability of SNOM-PiFM method to study the Infrared Radiation (IR) spectra of ultra-thin coatings with transparent substrates was proposed.
Segmentation, tracking, and sub-cellular feature extraction in 3D time-lapse images
Authors: Jiang Jiaxiang , Khan Amil , Shailja S. , Belteton Samuel A. , Goebel Michael , Szymanski Daniel B. , Manjunath B. S. 
Published: March 2023

AbstractThis paper presents a method for time-lapse 3D cell analysis. Specifically, we consider the problem of accurately localizing and quantitatively analyzing sub-cellular features, and for tracking individual cells from time-lapse 3D confocal cell image stacks. The heterogeneity of cells and the volume of multi-dimensional images presents a major challenge for fully automated analysis of morphogenesis and development of cells. This paper is motivated by the pavement cell growth process, and building a quantitative morphogenesis model. We propose a deep feature based segmentation method to accurately detect and label each cell region. An adjacency graph based method is used to extract sub-cellular features of the segmented cells. Finally, the robust graph based tracking algorithm using multiple cell features is proposed for associating cells at different time instances. We also demonstrate the generality of our tracking method on C. elegans fluorescent nuclei imagery. Extensive experiment results are provided and demonstrate the robustness of the proposed method. The code is available on and the method is available as a service through the BisQue portal.
Effect of liposomal formulation of ascorbic acid on corneal permeability
Authors: Csorba Anita , Katona Gábor , Budai-Szűcs Mária , Balogh-Weiser Diána , Fadda Anna Maria , Caddeo Carla , Takács Ágnes Ildikó , Mátyus Péter , Balogh György T. , Nagy Zoltán Zsolt 
Published: March 2023

AbstractAscorbic acid (AA) has a pivotal role in corneal wound healing via stimulating the biosynthesis of highly organized extracellular matrix components, but its rapid degradation and low corneal permeability limits its therapeutic effects. In this paper, we present the pharmacokinetic properties of a liposomal-based formulation of AA in terms of corneal permeation. Chemical stability, shelf-life, and drug release rate of lyophilized liposome (AA-LLipo) formulation was determined in comparison to free-form of AA solution using high-performance liquid chromatography (HPLC) and rapid equilibrium dialysis. In vitro transcorneal permeability was studied using a parallel artificial membrane permeability assay (PAMPA). Ex vivo permeation was examined on AA-LLipo-treated porcine cornea by determining the AA content on the ocular surface, in the cornea as well as in the aqueous humor using HPLC, and by Raman-mapping visualizing the AA-distribution. Our results showed that the liposomal formulation improved the chemical stability of AA, while drug release was observed with the same kinetic efficiency as from the free-form of AA solution. Both corneal-PAMPA and porcine corneal permeability studies showed that AA-LLipo markedly improved the corneal absorption kinetics of AA, thus, increasing the AA content in the cornea and aqueous humor. AA-LLipo formulation could potentially increase the bioavailability of AA in corneal tissues.
Comparative validation of AI and non-AI methods in MRI volumetry to diagnose Parkinsonian syndromes
Authors: Song Joomee , Hahm Juyoung , Lee Jisoo , Lim Chae Yeon , Chung Myung Jin , Youn Jinyoung , Cho Jin Whan , Ahn Jong Hyeon , Kim Kyungsu 
Published: March 2023

AbstractAutomated segmentation and volumetry of brain magnetic resonance imaging (MRI) scans are essential for the diagnosis of Parkinson’s disease (PD) and Parkinson’s plus syndromes (P-plus). To enhance the diagnostic performance, we adopt deep learning (DL) models in brain MRI segmentation and compared their performance with the gold-standard non-DL method. We collected brain MRI scans of healthy controls ($$n=105$$

n
=
105

) and patients with PD ($$n=105$$

n
=
105

), multiple systemic atrophy ($$n=132$$

n
=
132

), and progressive supranuclear palsy ($$n=69$$

n
=
69

) at Samsung Medical Center from January 2017 to December 2020. Using the gold-standard non-DL model, FreeSurfer (FS), we segmented six brain structures: midbrain, pons, caudate, putamen, pallidum, and third ventricle, and considered them as annotated data for DL models, the representative convolutional neural network (CNN) and vision transformer (ViT)-based models. Dice scores and the area under the curve (AUC) for differentiating normal, PD, and P-plus cases were calculated to determine the measure to which FS performance can be reproduced as-is while increasing speed by the DL approaches. The segmentation times of CNN and ViT for the six brain structures per patient were 51.26 ± 2.50 and 1101.82 ± 22.31 s, respectively, being 14 to 300 times faster than FS (15,735 ± 1.07 s). Dice scores of both DL models were sufficiently high (> 0.85) so their AUCs for disease classification were not inferior to that of FS. For classification of normal vs. P-plus and PD vs. P-plus (except multiple systemic atrophy - Parkinsonian type) based on all brain parts, the DL models and FS showed AUCs above 0.8, demonstrating the clinical value of DL models in addition to FS. DL significantly reduces the analysis time without compromising the performance of brain segmentation and differential diagnosis. Our findings may contribute to the adoption of DL brain MRI segmentation in clinical settings and advance brain research.
A portable, programmable, multichannel stimulator with high compliance voltage for noninvasive neural stimulation of motor and sensory nerves in humans
Authors: Trout Marshall A. , Harrison Abigail T. , Brinton Mark R. , George Jacob A. 
Published: March 2023

AbstractMost neural stimulators do not have a high enough compliance voltage to pass current through the skin. The few stimulators that meet the high compliance voltage necessary for transcutaneous stimulation are typically large benchtop units that are not portable, and the stimulation waveforms cannot be readily customized. To address this, we present the design and validation of a portable, programmable, multichannel, noninvasive neural stimulator that can generate three custom bipolar waveforms at ± 150 V with microsecond temporal resolution. The design is low-cost, open-source, and validated on the benchtop and with a healthy population to demonstrate its functionality for sensory and motor stimulation. Sensory stimulation included electrocutaneous stimulation targeting cutaneous mechanoreceptors at the surface of the skin and transcutaneous nerve stimulation targeting the median nerve at the wrist. Both electrocutaneous stimulation on the hand and transcutaneous stimulation at the wrist can elicit isolated tactile percepts on the hand but changes in pulse frequency are more discriminable for electrocutaneous stimulation. Also, neuromuscular electrical stimulation of the flexor digiti profundus is evoked by applying electrical stimulation directly above the muscle in the forearm and to the median and ulnar nerves in the upper arm. Muscle and nerve stimulation evoked similar grip forces and force rise times, but nerve stimulation had a significantly slower fatigue rate. The development and validation of this noninvasive stimulator and direct comparison of common sensory and motor stimulation targets in a human population constitute an important step towards more widespread use and accessibility of neural stimulation for education and research.
Comparison of neoadjuvant chemohormonal therapy vs. extended pelvic lymph-node dissection in high-risk prostate cancer treated with robot-assisted radical prostatectomy
Authors: Oishi Takuya , Hatakeyama Shingo , Tabata Ryuji , Fujimori Daiji , Fukuda Mamoru , Shinozaki Tetsuo , Ishii Noritaka , Iwamura Hiromichi , Okamoto Teppei , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Sato Satoshi , Ohyama Chikara 
Published: March 2023

AbstractWe compared the impact of treatment strategies on postoperative complications and prognosis between robot-assisted radical prostatectomy (RARP) plus extended pelvic lymph-node dissection (ePLND) and RARP plus neoadjuvant chemohormonal therapy (NCHT) without ePLND. We retrospectively evaluated 452 patients with high-risk prostate cancer (defined as any one of prostate-specific antigen ≥ 20 ng/mL, Gleason score 8–10, or cT2c–3) who were treated with RARP between January 2012 and February 2021. The patients were divided into two groups: RARP with ePLND (ePLND group) and NCHT plus RARP without ePLND (NCHT group). We compared the complication rate (Clavien–Dindo classification), biochemical recurrence-free survival, and castration-resistant prostate cancer (CRPC)-free survival between the groups. We performed multivariable Cox regression analysis using inverse probability weighting (IPTW) methods to assess the impact of the different treatments on prognosis. There were 150 and 302 patients in the ePLND and NCHT groups, respectively. The postoperative complication rate was significantly higher in the ePLND group than in the NCHT group (P < 0.001). IPTW-adjusted biochemical recurrence-free survival and CRPC-free survival were significantly higher in the NCHT group than in the ePLND group (hazard ratio [HR] 0.29, P < 0.001, and HR 0.29, P = 0.010, respectively). NCHT plus RARP without ePLND may reduce the risk of postoperative complications compared with ePLND during RARP. The impact of treatment strategies on oncological outcomes needs further studies.
Poor air passenger knowledge of COVID-19 symptoms and behaviour undermines strategies aimed at preventing the import of SARS-CoV-2 into the UK
Authors: Jones David. L. , Rhymes Jennifer M. , Green Emma , Rimmer Charlotte , Kevill Jessica L. , Malham Shelagh K. , Weightman Andrew J. , Farkas Kata 
Published: March 2023

AbstractAir travel mediates transboundary movement of SARS-CoV-2. To prepare for future pandemics, we sought to understand air passenger behaviour and perceived risk during the COVID-19 pandemic. This study of UK adults (n = 2103) quantified knowledge of COVID-19 symptoms, perceived health risk of contracting COVID-19, likelihood of returning to the UK with COVID-19 symptoms, likelihood to obey self-quarantining guidelines, how safe air travellers felt when flying during the pandemic (n = 305), and perceptions towards face covering effectiveness.Overall knowledge of COVID-19 symptoms was poor. Men and younger age groups (18–44) were less informed than women and older age groups (44 +). A significant proportion (21%) of the population would likely travel back to the UK whilst displaying COVID-19 symptoms with many expressing that they would not fully comply with self-isolation guidelines. Overall, males and younger age groups had a reduced perceived personal risk from contracting COVID-19, posing a higher risk of transporting SARS-CoV-2 back to the UK. Poor passenger knowledge and behaviour undermines government guidelines and policies aimed at preventing SARS-CoV-2 entry into the UK. This supports the need for stricter, clearer and more targeted guidelines with point-of-departure viral testing and stricter quarantining upon arrival.