bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization
Authors: Zhou Xun , Chen Hui , Hu Yan , Ma Xiaoyan , Li Jinqing , Shi Yingfeng , Tao Min , Wang Yi , Zhong Qin , Yan Danying , Zhuang Shougang , Liu Na
Published: April 2023

Long-term follow-up data indicates that 1/4 patients with acute kidney injury (AKI) will develop to chronic kidney disease (CKD). Our previous studies have demonstrated that enhancer of zeste homolog 2 (EZH2) played an important role in AKI and CKD. However, the role and mechanisms of EZH2 in AKI-to-CKD transition are still unclear. Here, we demonstrated EZH2 and H3K27me3 highly upregulated in kidney from patients with ANCA-associated glomerulonephritis, and expressed positively with fibrotic lesion and negatively with renal function. Conditional EZH2 deletion or pharmacological inhibition with 3-DZNeP significantly improved renal function and attenuated pathological lesion in ischemia/reperfusion (I/R) or folic acid (FA) mice models (two models of AKI-to-CKD transition). Mechanistically, we used CUT & Tag technology to verify that EZH2 binding to the PTEN promoter and regulating its transcription, thus regulating its downstream signaling pathways. Genetic or pharmacological depletion of EZH2 upregulated PTEN expression and suppressed the phosphorylation of EGFR and its downstream signaling ERK1/2 and STAT3, consequently alleviating the partial epithelial-mesenchymal transition (EMT), G2/M arrest, and the aberrant secretion of profibrogenic and proinflammatory factors in vivo and vitro experiments. In addition, EZH2 promoted the EMT program induced loss of renal tubular epithelial cell transporters (OAT1, ATPase, and AQP1), and blockade of EZH2 prevented it. We further co-cultured macrophages with the medium of human renal tubular epithelial cells treated with H2O2 and found macrophages transferred to M2 phenotype, and EZH2 could regulate M2 macrophage polarization through STAT6 and PI3K/AKT pathways. These results were further verified in two mice models. Thus, targeted inhibition of EZH2 might be a novel therapy for ameliorating renal fibrosis after acute kidney injury by counteracting partial EMT and blockade of M2 macrophage polarization.
Combinatorial gene therapy for epilepsy: Gene sequence positioning and AAV serotype influence expression and inhibitory effect on seizures
Authors: Melin Esbjörn , Andersson My , Gøtzsche Casper R. , Wickham Jenny , Huang Yuzhe , Szczygiel Julia Alicja , Boender Arnie , Christiansen Søren H. , Pinborg Lars , Woldbye David P. D. , Kokaia Merab
Published: April 2023

Gene therapy with AAV vectors carrying genes for neuropeptide Y and its receptor Y2 has been shown to inhibit seizures in multiple animal models of epilepsy. It is however unknown how the AAV serotype or the sequence order of these two transgenes in the expression cassette affects the actual parenchymal gene expression levels and the seizure-suppressant efficacy. To address these questions, we compared three viral vector serotypes (AAV1, AAV2 and AAV8) and two transgene sequence orders (NPY-IRES-Y2 and Y2-IRES-NPY) in a rat model of acutely induced seizures. Wistar male rats were injected bilaterally with viral vectors and 3 weeks later acute seizures were induced by a subcutaneous injection of kainate. The latency until 1st motor seizure, time spent in motor seizure and latency to status epilepticus were measured to evaluate the seizure-suppressing efficacy of these vectors compared to an empty cassette control vector. Based on the results, the effect of the AAV1-NPY-IRES-Y2 vector was further investigated by in vitro electrophysiology, and its ability to achieve transgene overexpression in resected human hippocampal tissue was evaluated. The AAV1-NPY-IRES-Y2 proved to be better to any other serotype or gene sequence considering both transgene expression and ability to suppress induced seizures in rats. The vector also demonstrated transgene-induced decrease of glutamate release from excitatory neuron terminals and significantly increased both NPY and Y2 expression in resected human hippocampal tissue from patients with drug-resistant temporal lobe epilepsy. These results validate the feasibility of NPY/Y2 receptor gene therapy as a therapeutic opportunity in focal epilepsies.
Chasing the spin gap through the phase diagram of a frustrated Mott insulator
Authors: Pustogow A. , Kawasugi Y. , Sakurakoji H. , Tajima N.
Published: April 2023

The quest for entangled spin excitations has stimulated intense research on frustrated magnetic systems. For almost two decades, the triangular-lattice Mott insulator κ-(BEDT-TTF)2Cu2(CN)3 has been one of the hottest candidates for a gapless quantum spin liquid with itinerant spinons. Very recently, however, this scenario was overturned as electron-spin-resonance (ESR) studies unveiled a spin gap, calling for reevaluation of the magnetic ground state. Here we achieve a precise mapping of this spin-gapped phase through the Mott transition by ultrahigh-resolution strain tuning. Our transport experiments reveal a reentrance of charge localization below T⋆ = 6 K associated with a gap size of 30–50 K. The negative slope of the insulator-metal boundary, dT⋆/dp < 0, evidences the low-entropy nature of the spin-singlet ground state. By tuning the enigmatic ‘6K anomaly’ through the phase diagram of κ-(BEDT-TTF)2Cu2(CN)3, we identify it as the transition to a valence-bond-solid phase, in agreement with previous thermal expansion and magnetic resonance studies. This spin-gapped insulating state persists at T → 0 until unconventional superconductivity and metallic transport proliferate.
Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers
Authors: ter Brugge Petra , Moser Sarah C. , Bièche Ivan , Kristel Petra , Ibadioune Sabrina , Eeckhoutte Alexandre , de Bruijn Roebi , van der Burg Eline , Lutz Catrin , Annunziato Stefano , de Ruiter Julian , Masliah Planchon Julien , Vacher Sophie , Courtois Laura , El-Botty Rania , Dahmani Ahmed , Montaudon Elodie , Morisset Ludivine , Sourd Laura , Huguet Léa , Derrien Heloise , Nemati Fariba , Chateau-Joubert Sophie , Larcher Thibaut , Salomon Anne , Decaudin Didier , Reyal Fabien , Coussy Florence , Popova Tatiana , Wesseling Jelle , Stern Marc-Henri , Jonkers Jos , Marangoni Elisabetta
Published: April 2023

The high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response.
Testing electron–phonon coupling for the superconductivity in kagome metal CsV3Sb5
Authors: Zhong Yigui , Li Shaozhi , Liu Hongxiong , Dong Yuyang , Aido Kohei , Arai Yosuke , Li Haoxiang , Zhang Weilu , Shi Youguo , Wang Ziqiang , Shin Shik , Lee H. N. , Miao H. , Kondo Takeshi , Okazaki Kozo
Published: April 2023

In crystalline materials, electron-phonon coupling (EPC) is a ubiquitous many-body interaction that drives conventional Bardeen-Cooper-Schrieffer superconductivity. Recently, in a new kagome metal CsV3Sb5, superconductivity that possibly intertwines with time-reversal and spatial symmetry-breaking orders is observed. Density functional theory calculations predicted weak EPC strength, λ, supporting an unconventional pairing mechanism in CsV3Sb5. However, experimental determination of λ is still missing, hindering a microscopic understanding of the intertwined ground state of CsV3Sb5. Here, using 7-eV laser-based angle-resolved photoemission spectroscopy and Eliashberg function analysis, we determine an intermediate λ=0.45–0.6 atT = 6 K for both Sb 5pand V 3delectronic bands, which can support a conventional superconducting transition temperature on the same magnitude of experimental value in CsV3Sb5. Remarkably, the EPC on the V 3d-band enhances to λ~0.75 as the superconducting transition temperature elevated to 4.4 K in Cs(V0.93Nb0.07)3Sb5. Our results provide an important clue to understand the pairing mechanism in the kagome superconductor CsV3Sb5.
Year-round utilization of sea ice-associated carbon in Arctic ecosystems
Authors: Koch Chelsea W. , Brown Thomas A. , Amiraux Rémi , Ruiz-Gonzalez Carla , MacCorquodale Maryam , Yunda-Guarin Gustavo A. , Kohlbach Doreen , Loseto Lisa L. , Rosenberg Bruno , Hussey Nigel E. , Ferguson Steve H. , Yurkowski David J.
Published: April 2023

Sea ice primary production is considered a valuable energy source for Arctic marine food webs, yet the extent remains unclear through existing methods. Here we quantify ice algal carbon signatures using unique lipid biomarkers in over 2300 samples from 155 species including invertebrates, fish, seabirds, and marine mammals collected across the Arctic shelves. Ice algal carbon signatures were present within 96% of the organisms investigated, collected year-round from January to December, suggesting continuous utilization of this resource despite its lower proportion to pelagic production. These results emphasize the importance of benthic retention of ice algal carbon that is available to consumers year-round. Finally, we suggest that shifts in the phenology, distribution and biomass of sea ice primary production anticipated with declining seasonal sea ice will disrupt sympagic-pelagic-benthic coupling and consequently the structure and the functioning of the food web which is critical for Indigenous Peoples, commercial fisheries, and global biodiversity.
Crystal structure of a highly conserved enteroviral 5′ cloverleaf RNA replication element
Authors: Das Naba K. , Hollmann Nele M. , Vogt Jeff , Sevdalis Spiridon E. , Banna Hasan A. , Ojha Manju , Koirala Deepak
Published: April 2023

The extreme 5′-end of the enterovirus RNA genome contains a conserved cloverleaf-like domain that recruits 3CD and PCBP proteins required for initiating genome replication. Here, we report the crystal structure at 1.9 Å resolution of this domain from the CVB3 genome in complex with an antibody chaperone. The RNA folds into an antiparallel H-type four-way junction comprising four subdomains with co-axially stacked sA-sD and sB-sC helices. Long-range interactions between a conserved A40 in the sC-loop and Py-Py helix within the sD subdomain organize near-parallel orientations of the sA-sB and sC-sD helices. Our NMR studies confirm that these long-range interactions occur in solution and without the chaperone. The phylogenetic analyses indicate that our crystal structure represents a conserved architecture of enteroviral cloverleaf-like domains, including the A40 and Py-Py interactions. The protein binding studies further suggest that the H-shape architecture provides a ready-made platform to recruit 3CD and PCBP2 for viral replication.
Intermittent fasting modulates the intestinal microbiota and improves obesity and host energy metabolism
Authors: Hu Xiangwei , Xia Kai , Dai Minhui , Han Xiaofeng , Yuan Peng , Liu Jia , Liu Shiwei , Jia Fuhuai , Chen Jiayu , Jiang Fangfang , Yu Jieyao , Yang Huanming , Wang Jian , Xu Xun , Jin Xin , Kristiansen Karsten , Xiao Liang , Chen Wei , Han Mo , Duan Shenglin
Published: April 2023

Abstract

Intermittent fasting (IF) is a promising paradigm for weight loss which has been shown to modulate the gut microbiota based on 16S rRNA gene amplicon sequencing. Here, 72 Chinese volunteers with a wide range of body mass index (BMI) participated in a three-week IF program during which an average loss of 3.67 kg body weight accompanied with improved clinical parameters was observed irrespective of initial anthropometric and gut microbiota status. Fecal samples were collected before and after the intervention and subjected to shotgun metagenomic sequencing. De novo assembly yielded 2934 metagenome-assembled genomes (MAGs). Profiling revealed significant enrichment of Parabacteroides distasonis and Bacteroides thetaiotaomicron after the intervention, with inverse correlations between their relative abundances and parameters related to obesity and atherosclerotic cardiovascular diseases (ASCVD). MAGs enriched after the intervention showed high richness and diversity of carbohydrate-active enzymes, with an increased relative abundances of genes related to succinate production and glutamate fermentation.
Identifying breast cancer patients at risk of relapse despite pathological complete response after neoadjuvant therapy
Authors: Huober Jens , van Mackelenbergh Marion , Schneeweiss Andreas , Seither Fenja , Blohmer Jens-Uwe , Denkert Carsten , Tesch Hans , Hanusch Claus , Salat Christoph , Rhiem Kerstin , Solbach Christine , Fasching Peter A. , Jackisch Christian , Reinisch Mattea , Lederer Bianca , Mehta Keyur , Link Theresa , Nekljudova Valentina , Loibl Sibylle , Untch Michael
Published: April 2023

This retrospective pooled analysis aims to identify factors predicting relapse despite a pathologic complete response (pCR) in patients with breast cancer (BC). 2066 patients with a pCR from five neoadjuvant GBG/AGO-B trials fulfill the inclusion criteria of this analysis. Primary endpoint is disease-free survival (DFS); secondary endpoints is distant DFS (DDFS) and overall survival (OS). After a median follow-up of 57.6 months, DFS is significantly worse for patients with positive lymph nodes (cN+ vs cN0 hazard ratio [HR] 1.94, 95%CI 1.48–2.54; p < 0.001). In patients with triple-negative tumors, lobular histology (lobular vs other HR 3.55, 95%CI 1.53–8.23; p = 0.003), and clinical nodal involvement (cN+ vs cN0 HR 2.45, 95%CI 1.59–3.79; p < 0.001) predict a higher risk of DFS events. Patients with HER2-positive cT3/4 tumors have a significantly higher risk of relapse (cT3/4 vs cT1 HR 2.07, 95%CI 1.06–4.03; p = 0.033). Initial tumor load and histological type predict relapse in patients with a pCR.
High-dimensional immune cell profiling of cerebrospinal fluid from patients with metastatic breast cancer and leptomeningeal disease
Authors: Im K. W. , Huppert L. A. , Malevanchik L. , Rugo H. S. , Combes A. J. , Campbell M. J. , Krummel M. F. , Melisko M. E.
Published: April 2023

Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). In this non-therapeutic study, we enrolled 12 patients with MBC and known or suspected LMD who were undergoing a lumbar puncture as part of clinical care and collected extra cerebrospinal fluid (CSF) and a paired blood sample from each patient at a single time point. Of the 12 patients, 7 patients are confirmed to have LMD based on positive cytology and/or convincing MRI imaging (LMDpos), and 5 patients are deemed not to have LMD based on similar criteria (LMDneg). Using high-dimensional, multiplexed flow cytometry, we profile and compare the CSF and peripheral blood mononuclear cell (PBMCs) immune populations between patients with LMD and those without. Patients with LMD observe a lower overall frequency of CD45+ cells (29.51% vs. 51.12%, p < 0.05), lower frequencies of CD8+ T cells (12.03% vs. 30.40%, p < 0.01), and higher frequency of Tregs than patients without LMD. Interestingly, the frequency of partially exhausted CD8+ T cells (CD38hiTIM3lo) is ~6.5-fold higher among patients with LMD vs. those without (2.99% vs. 0.44%, p < 0.05). Taken together, these data suggest that patients with LMD may have lower overall immune infiltrates than patients without LMD, suggesting a more permissive CSF immune microenvironment but a higher frequency of partially exhausted CD8+ T cells, which may offer an important therapeutic target.
A critical examination of robustness and generalizability of machine learning prediction of materials properties
Authors: Li Kangming , DeCost Brian , Choudhary Kamal , Greenwood Michael , Hattrick-Simpers Jason
Published: April 2023

Recent advances in machine learning (ML) have led to substantial performance improvement in material database benchmarks, but an excellent benchmark score may not imply good generalization performance. Here we show that ML models trained on Materials Project 2018 can have severely degraded performance on new compounds in Materials Project 2021 due to the distribution shift. We discuss how to foresee the issue with a few simple tools. Firstly, the uniform manifold approximation and projection (UMAP) can be used to investigate the relation between the training and test data within the feature space. Secondly, the disagreement between multiple ML models on the test data can illuminate out-of-distribution samples. We demonstrate that the UMAP-guided and query by committee acquisition strategies can greatly improve prediction accuracy by adding only 1% of the test data. We believe this work provides valuable insights for building databases and models that enable better robustness and generalizability.
Oxidative dissolution of Cr-doped UO2 nuclear fuel
Authors: Smith Hannah , Cordara Théo , Gausse Clémence , Pepper Sarah E. , Corkhill Claire L.
Published: April 2023

Alternative UO2 nuclear fuels, incorporating Cr as a dopant, are currently in use in light–water reactors. Dissolution experiments using Cr-doped UO2, performed as a function of Cr content in a simplified groundwater solution and under oxic conditions, established that the addition of Cr to the UO2 matrix systematically reduced the normalised dissolution rate of U at 25 and 40 °C. This effect was most notable under dilute solution conditions, and is the result of galvanic coupling between Cr and U, resulting from the presence of Cr2+ in the UO2 matrix, as corroborated by activation energy determination. Under conditions of solution saturation, where schoepite ((UO2)8O2(OH)12·(H2O)12) and Na2U2O7·6H2O were identified as secondary phases, the rate of U dissolution was invariant with Cr content. Moreover, at 60 °C, the trend was reversed and the rate of U dissolution increased with increasing Cr content. Under these conditions, other factors, including U solubility or bicarbonate-surface interactions, exert a stronger influence on the U dissolution kinetics than Cr. Increased grain size, a feature of Cr-doped UO2 fuel, was also found to reduce the normalised dissolution rate of U. In establishing the mechanisms by which Cr dopants influence UO2 fuel dissolution, it can be concluded that, overall, Cr-doped UO2 nuclear fuel possesses similar dissolution kinetics to undoped UO2 fuel, giving confidence for its eventual disposal in a geological facility.
Neuroprotective actions of a fatty acid nitroalkene in Parkinson’s disease
Authors: Di Maio Roberto , Keeney Matthew T. , Cechova Veronika , Mortimer Amanda , Sekandari Ahssan , Rowart Pascal , Greenamyre J. Timothy , Freeman Bruce A. , Fazzari Marco
Published: April 2023

To date there are no therapeutic strategies that limit the progression of Parkinson’s disease (PD). The mechanisms underlying PD-related nigrostriatal neurodegeneration remain incompletely understood, with multiple factors modulating the course of PD pathogenesis. This includes Nrf2-dependent gene expression, oxidative stress, α-synuclein pathology, mitochondrial dysfunction, and neuroinflammation. In vitro and sub-acute in vivo rotenone rat models of PD were used to evaluate the neuroprotective potential of a clinically-safe, multi-target metabolic and inflammatory modulator, the electrophilic fatty acid nitroalkene 10-nitro-oleic acid (10-NO2-OA). In N27-A dopaminergic cells and in the substantia nigra pars compacta of rats, 10-NO2-OA activated Nrf2-regulated gene expression and inhibited NOX2 and LRRK2 hyperactivation, oxidative stress, microglial activation, α-synuclein modification, and downstream mitochondrial import impairment. These data reveal broad neuroprotective actions of 10-NO2-OA in a sub-acute model of PD and motivate more chronic studies in rodents and primates.
Towards practical and massively parallel quantum computing emulation for quantum chemistry
Authors: Shang Honghui , Fan Yi , Shen Li , Guo Chu , Liu Jie , Duan Xiaohui , Li Fang , Li Zhenyu
Published: April 2023

Quantum computing is moving beyond its early stage and seeking for commercial applications in chemical and biomedical sciences. In the current noisy intermediate-scale quantum computing era, the quantum resource is too scarce to support these explorations. Therefore, it is valuable to emulate quantum computing on classical computers for developing quantum algorithms and validating quantum hardware. However, existing simulators mostly suffer from the memory bottleneck so developing the approaches for large-scale quantum chemistry calculations remains challenging. Here we demonstrate a high-performance and massively parallel variational quantum eigensolver (VQE) simulator based on matrix product states, combined with embedding theory for solving large-scale quantum computing emulation for quantum chemistry on HPC platforms. We apply this method to study the torsional barrier of ethane and the quantification of the protein–ligand interactions. Our largest simulation reaches 1000 qubits, and a performance of 216.9 PFLOP/s is achieved on a new Sunway supercomputer, which sets the state-of-the-art for quantum computing emulation for quantum chemistry.
Endothelial Brg1 fine-tunes Notch signaling during zebrafish heart regeneration
Authors: Xiao Chenglu , Hou Junjie , Wang Fang , Song Yabing , Zheng Jiyuan , Luo Lingfei , Wang Jianbin , Ding Wanqiu , Zhu Xiaojun , Xiong Jing-Wei
Published: April 2023

Myocardial Brg1 is essential for heart regeneration in zebrafish, but it remains unknown whether and how endothelial Brg1 plays a role in heart regeneration. Here, we found that bothbrg1mRNA and protein were induced in cardiac endothelial cells after ventricular resection and endothelium-specific overexpression of dominant-negativeXenopusBrg1 (dn-xbrg1) inhibited myocardial proliferation and heart regeneration and increased cardiac fibrosis. RNA-seq and ChIP-seq analysis revealed that endothelium-specific overexpression ofdn-xbrg1changed the levels of H3K4me3 modifications in the promoter regions of the zebrafish genome and induced abnormal activation of Notch family genes upon injury. Mechanistically, Brg1 interacted with lysine demethylase 7aa (Kdm7aa) to fine-tune the level of H3K4me3 within the promoter regions of Notch family genes and thus regulatednotchgene transcription. Together, this work demonstrates that the Brg1-Kdm7aa-Notch axis in cardiac endothelial cells, including the endocardium, regulates myocardial proliferation and regeneration via modulating the H3K4me3 of thenotchpromoters in zebrafish.
Topographical mapping of catecholaminergic axon innervation in the flat-mounts of the mouse atria: a quantitative analysis
Authors: Zhang Yuanyuan , Bizanti Ariege , Harden Scott W. , Chen Jin , Bendowski Kohlton , Hoover Donald B. , Gozal David , Shivkumar Kalyanam , Heal Maci , Tappan Susan , Cheng Zixi Jack
Published: April 2023

The sympathetic nervous system is crucial for controlling multiple cardiac functions. However, a comprehensive, detailed neuroanatomical map of the sympathetic innervation of the heart is unavailable. Here, we used a combination of state-of-the-art techniques, including flat-mount tissue processing, immunohistochemistry for tyrosine hydroxylase (TH, a sympathetic marker), confocal microscopy and Neurolucida 360 software to trace, digitize, and quantitatively map the topographical distribution of the sympathetic postganglionic innervation in whole atria of C57Bl/6 J mice. We found that (1) 4–5 major extrinsic TH-IR nerve bundles entered the atria at the superior vena cava, right atrium (RA), left precaval vein and the root of the pulmonary veins (PVs) in the left atrium (LA). Although these bundles projected to different areas of the atria, their projection fields partially overlapped. (2) TH-IR axon and terminal density varied considerably between different sites of the atria with the greatest density of innervation near the sinoatrial node region (P < 0.05, n = 6). (3) TH-IR axons also innervated blood vessels and adipocytes. (4) Many principal neurons in intrinsic cardiac ganglia and small intensely fluorescent cells were also strongly TH-IR. Our work provides a comprehensive topographical map of the catecholaminergic efferent axon morphology, innervation, and distribution in the whole atria at single cell/axon/varicosity scale that may be used in future studies to create a cardiac sympathetic-brain atlas.
Extension of bacterial rDNA sequencing for simultaneous methylation detection and its application in microflora analysis
Authors: Nishimura Motoi , Tanaka Tomoaki , Murata Syota , Miyabe Akiko , Ishige Takayuki , Kawasaki Kenji , Yokoyama Masataka , Hashimoto Naoko , Yamagata Kazuyuki , Nagano Hidekazu , Tojo-Nishimura Satomi , Matsushita Kazuyuki
Published: April 2023

Although polymerase chain reaction (PCR) amplification and sequencing of the bacterial 16S rDNA region has numerous scientific applications, it does not provide DNA methylation information. Herein, we propose a simple extension for bisulfite sequencing to investigate 5-methylcytosine residues in the bacterial 16S rDNA region from clinical isolates or flora. Multiple displacement amplification without DNA denaturation was used to preferentially pre-amplify single-stranded bacterial DNA after bisulfite conversion. Following the pre-amplification, the 16S rDNA region was analyzed using nested bisulfite PCR and sequencing, enabling the simultaneous identification of DNA methylation status and sequence data. We used this approach (termed sm16S rDNA PCR/sequencing) to identify novel methylation sites and a methyltransferase (M. MmnI) in Morganella morganii and different methylation motifs among Enterococcus faecalis strains from small volumes of clinical specimens. Further, our analysis suggested that M. MmnI may be correlated to erythromycin resistance. Thus, sm16S rDNA PCR/sequencing is a useful extension method for analyzing the DNA methylation of 16S rDNA regions in a microflora, providing additional information not provided by conventional PCR. Given the relationship between DNA methylation status and drug resistance in bacteria, we believe this technique can be effectively applied in clinical sample testing.
Asperuloside attenuates cadmium-induced toxicity by inhibiting oxidative stress, inflammation, fibrosis and apoptosis in rats
Authors: Kong Zhiyang , Liu Chunhong , Olatunji Opeyemi Joshua
Published: April 2023

This present study investigated the protective effects of asperuloside (ASP) against cadmium-induced nephrocardiac toxicity. Rats were treated with 50 mg/kg of ASP for five weeks and CdCl2 (5 mg/kg, p.o., once daily) during the last 4 weeks of ASP treatment. The serum levels of blood urea nitrogen (BUN), creatinine (Scr), aspartate transaminase (AST), creatine kinase-MB (CK-MB), troponin T (TnT) and lactate dehydrogenase (LDH) were evealuted. Oxido-inflammatory parameters were detected via malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1beta (IL-1β) and nuclear factor kappa B (NF-κB). Additionally, the cardiorenal levels of caspase 3, transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA), collagen IV and Bcl2 were measured by ELISA or immunohistochemical assays. The results indicated that ASP significantly decreased Cd-instigated oxidative stress, serum BUN, Scr, AST, CK-MB, TnT and LDH as well as histopathological alterations. Furthermore, ASP notably attenuated Cd-induced cardiorenal and apoptosis and fibrosis by reducing caspase 3 and TGF-β levels, as well as reducing the stain intensity of a-SMA and collagen IV, while increasing Bcl2 intensity. These results revealed that ASP attenuated Cd induced cardiac and renal toxicity which may be attributed to reducing oxidative stress, inflammation, fibrosis and apoptosis.
Influence of the hierarchical architecture of multi-core iron oxide nanoflowers on their magnetic properties
Authors: Neumann Stefan , Kuger Laura , Arlt Carsten-Rene , Franzreb Matthias , Rafaja David
Published: April 2023

Magnetic properties of superparamagnetic iron oxide nanoparticles are controlled mainly by their particle size and by their particle size distribution. Magnetic properties of multi-core iron oxide nanoparticles, often called iron oxide nanoflowers (IONFs), are additionally affected by the interaction of magnetic moments between neighboring cores. The knowledge about the hierarchical structure of IONFs is therefore essential for understanding the magnetic properties of IONFs. In this contribution, the architecture of multi-core IONFs was investigated using correlative multiscale transmission electron microscopy (TEM), X-ray diffraction and dynamic light scattering. The multiscale TEM measurements comprised low-resolution and high-resolution imaging as well as geometric phase analysis. The IONFs contained maghemite with the average chemical composition $$\gamma$$
γ
-Fe$$_{2.72\pm 0.02}$$

2.72
±
0.02

O$$_4$$

4

. The metallic vacancies located on the octahedral lattice sites of the spinel ferrite structure were partially ordered. Individual IONFs consisted of several cores showing frequently a specific crystallographic orientation relationship between direct neighbors. This oriented attachment may facilitate the magnetic alignment within the cores. Individual cores were composed of partially coherent nanocrystals having almost the same crystallographic orientation. The sizes of individual constituents revealed by the microstructure analysis were correlated with the magnetic particle sizes that were obtained from fitting the measured magnetization curve by the Langevin function.
Real-time respiratory motion prediction using photonic reservoir computing
Authors: Liang Zhizhuo , Zhang Meng , Shi Chengyu , Huang Z. Rena
Published: April 2023

Respiration induced motion is a well-recognized challenge in many clinical practices including upper body imaging, lung tumor motion tracking and radiation therapy. In this work, we present a recurrent neural network algorithm that was implemented in a photonic delay-line reservoir computer (RC) for real-time respiratory motion prediction. The respiratory motion signals are quasi-periodic waveforms subject to a variety of non-linear distortions. In this work, we demonstrated for the first time that RC can be effective in predicting short to medium range of respiratory motions within practical timescales. A double-sliding window technology is explored to enable the real-time establishment of an individually trained model for each patient and the real-time processing of live-streamed respiratory motion data. A breathing dataset from a total of 76 patients with breathing speeds ranging from 3 to 20 breaths per minute (BPM) is studied. Motion prediction of look-ahead times of 66.6, 166.6, and 333 ms are investigated. With a 333 ms look-ahead time, the real-time RC model achieves an average normalized mean square error (NMSE) of 0.025, an average mean absolute error (MAE) of 0.34 mm, an average root mean square error (RMSE) of 0.45 mm, an average therapeutic beam efficiency (TBE) of 94.14% for an absolute error (AE) < 1 mm, and 99.89% for AE < 3 mm. This study demonstrates that real-time RC is an efficient computing framework for high precision respiratory motion prediction.
The impact of pericytes on the stability of microvascular networks in response to nanoparticles
Authors: Dibble Matthew , Di Cio’ Stefania , Luo Piaopiao , Balkwill Frances , Gautrot Julien E.
Published: April 2023

Recapitulating the normal physiology of the microvasculature is pivotal in the development of more complex in-vitro models and organ-on-chip designs. Pericytes are an important component of the vasculature, promoting vessel stability, inhibiting vascular permeability and maintaining the vascular hierarchical architecture. The use of such co-culture for the testing of therapeutics and nanoparticle safety is increasingly considered for the validation of therapeutic strategies. This report presents the use of a microfluidic model for such applications. Interactions between endothelial cells and pericytes are first explored. We identify basal conditions required to form stable and reproducible endothelial networks. We then investigate interactions between endothelial cells and pericytes via direct co-culture. In our system, pericytes prevented vessel hyperplasia and maintained vessel length in prolonged culture (> 10 days). In addition, these vessels displayed barrier function and expression of junction markers associated with vessel maturation, including VE-cadherin, β-catenin and ZO-1. Furthermore, pericytes maintained vessel integrity following stress (nutrient starvation) and prevented vessel regression, in contrast to the striking dissociation of networks in endothelial monocultures. This response was also observed when endothelial/pericyte co-cultures were exposed to high concentrations of moderately toxic cationic nanoparticles used for gene delivery. This study highlights the importance of pericytes in protecting vascular networks from stress and external agents and their importance to the design of advanced in-vitro models, including for the testing of nanotoxicity, to better recapitulate physiological response and avoid false positives.
Marginal leaf galls on Pliocene leaves from India indicate mutualistic behavior between Ipomoea plants and Eriophyidae mites
Authors: Hazra Taposhi , Adroit Benjamin , Denk Thomas , Wappler Torsten , Sarkar Subhankar Kumar , Bera Subir , Khan Mahasin Ali
Published: April 2023

We report a new type of fossil margin galls arranged in a linear series on dicot leaf impressions from the latest Neogene (Pliocene) sediments of the Chotanagpur Plateau, Jharkhand, eastern India. We collected ca. 1500 impression and compression leaf fossils, of which 1080 samples bear arthropod damage referable to 37 different damage types (DT) in the ‘GuidetoInsect(andOther)DamageTypesinCompressedPlantFossils’. A few leaf samples identified as Ipomoea L. (Convolvulaceae) have specific margin galls that do not match any galling DT previously described. This type of galling is characterized by small, linearly arranged, irregular, sessile, sub-globose, solitary, indehiscent, solid pouch-galls with irregular ostioles. The probable damage inducers of the present galling of the foliar margin might be members of Eriophyidae (Acari). The new type of gall suggests that marginal gall-inducing mites on leaves of Ipomoea did not change their host preference at the genus level since the Pliocene. The development of marginal leaf galling in Ipomoea is linked to extrafloral nectaries that do not offer protection against arthropod galling but indirectly protect the plant against herbivory from large mammals.
Two-generation exposure to a high-fat diet induces the change of salty taste preference in rats
Authors: Serirukchutarungsee Saranya , Watari Ippei , Narukawa Masataka , Podyma-Inoue Katarzyna Anna , Sangsuriyothai Pornchanok , Ono Takashi
Published: April 2023

High-fat diet (HFD) leads to multiple complications, including taste alteration. This study observed the effect of a two-generation exposure to an HFD on the peripheral taste system in offspring. Ten pregnant Wistar rats were assigned a standard diet (SD) (n = 5) or HFD (n = 5) from day 7 of pregnancy through the lactation. Thirty-six male and female 3-week-old offspring were measured for body weight and blood glucose level, and the circumvallate papillae were collected. The other twenty-four 3-week-old offspring were weaned on the same diet as their mothers and raised individually. The taste preference behaviors were studied using the two-bottle taste preference test and analyzed five basic tastes (sweet, bitter, umami, sour, and salty). The expressions of epithelial sodium channel alpha subunit (ENaCα) and angiotensin II receptor type 1 (AT1) in the circumvallate papilla were analyzed by immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). We found increased body weight and salty taste preference of offspring from the HFD group in both sexes. Correspondingly, the AT1 level of the taste bud cells significantly increased in 3-week-old female offspring from the HFD group. An increase in AT1 levels may be a risk factor for changes in salty taste preference.
Application of machine learning algorithm in predicting distant metastasis of T1 gastric cancer
Authors: Tian HuaKai , Liu Zitao , Liu Jiang , Zong Zhen , Chen YanMei , Zhang Zuo , Li Hui
Published: April 2023

Distant metastasis (DM) is relatively uncommon in T1 stage gastric cancer (GC). The aim of this study was to develop and validate a predictive model for DM in stage T1 GC using machine learning (ML) algorithms. Patients with stage T1 GC from 2010 to 2017 were screened from the public Surveillance, Epidemiology and End Results (SEER) database. Meanwhile, we collected patients with stage T1 GC admitted to the Department of Gastrointestinal Surgery of the Second Affiliated Hospital of Nanchang University from 2015 to 2017. We applied seven ML algorithms: logistic regression, random forest (RF), LASSO, support vector machine, k-Nearest Neighbor, Naive Bayesian Model, Artificial Neural Network. Finally, a RF model for DM of T1 GC was developed. The AUC, sensitivity, specificity, F1-score and accuracy were used to evaluate and compare the predictive performance of the RF model with other models. Finally, we performed a prognostic analysis of patients who developed distant metastases. Independent risk factors for prognosis were analysed by univariate and multifactorial regression. K-M curves were used to express differences in survival prognosis for each variable and subvariable. A total of 2698 cases were included in the SEER dataset, 314 with DM, and 107 hospital patients were included, 14 with DM. Age, T-stage, N-stage, tumour size, grade and tumour location were independent risk factors for the development of DM in stage T1 GC. A combined analysis of seven ML algorithms in the training and test sets found that the RF prediction model had the best prediction performance (AUC: 0.941, Accuracy: 0.917, Recall: 0.841, Specificity: 0.927, F1-score: 0.877). The external validation set ROCAUC was 0.750. Meanwhile, survival prognostic analysis showed that surgery (HR = 3.620, 95% CI 2.164–6.065) and adjuvant chemotherapy (HR = 2.637, 95% CI 2.067–3.365) were independent risk factors for survival prognosis in patients with DM from stage T1 GC. Age, T-stage, N-stage, tumour size, grade and tumour location were independent risk factors for the development of DM in stage T1 GC. ML algorithms had shown that RF prediction models had the best predictive efficacy to accurately screen at-risk populations for further clinical screening for metastases. At the same time, aggressive surgery and adjuvant chemotherapy can improve the survival rate of patients with DM.
Microstructural segmentation using a union of attention guided U-Net models with different color transformed images
Authors: Biswas Momojit , Pramanik Rishav , Sen Shibaprasad , Sinitca Aleksandr , Kaplun Dmitry , Sarkar Ram
Published: April 2023

Metallographic images or often called the microstructures contain important information about metals, such as strength, toughness, ductility, corrosion resistance, which are used to choose the proper materials for various engineering applications. Thus by understanding the microstructures, one can determine the behaviour of a component made of a particular metal, and can predict the failure of that component in certain conditions. Image segmentation is a powerful technique for determination of morphological features of the microstructure like volume fraction, inclusion morphology, void, and crystal orientations. These are some key factors for determining the physical properties of metal. Therefore, automatic micro-structure characterization using image processing is useful for industrial applications which currently adopts deep learning-based segmentation models. In this paper, we propose a metallographic image segmentation method using an ensemble of modified U-Nets. Three U-Net models having the same architecture are separately fed with color transformed imaged (RGB, HSV and YUV). We improvise the U-Net with dilated convolutions and attention mechanisms to get finer grained features. Then we apply the sum-rule-based ensemble method on the outcomes of U-Net models to get the final prediction mask. We achieve the mean intersection over union (IoU) score of 0.677 on a publicly available standard dataset, namely MetalDAM. We also show that the proposed method obtains results comparable to state-of-the-art methods with fewer number of model parameters. The source code of the proposed work can be found at https://github.com/mb16biswas/attention-unet.
Cardiac ischemia and reperfusion in mice: a comprehensive hemodynamic, electrocardiographic and electrophysiological characterization
Authors: Clasen Lukas , Angendohr Stephan , Becher Stefanie , Bartsch Benedikt , Enkel Stephan , Meyer Christian , Kelm Malte , Makimoto Hisaki , Klöcker Nikolaj
Published: April 2023

Malignant ventricular arrhythmias (VA) after acute myocardial infarction remain a major threat. Aim of this study was to characterize the electrophysiological and autonomic sequelae of cardiac ischemia and reperfusion (I/R) in mice during the first week post incident. Left ventricular function was serially assessed using transthoracic echocardiography. VA were quantified by telemetric electrocardiogram (ECG) recordings and electrophysiological studies on the 2nd and 7th day after I/R. Cardiac autonomic function was evaluated by heart rate variability (HRV) and heart rate turbulence (HRT). Infarct size was quantified by planimetric measures. I/R caused significant myocardial scarring and diminished left ventricular ejection fraction. The ECG intervals QRS, QT, QTc, and JTc were prolonged in I/R mice. Both spontaneous VA scored higher and the inducibility of VA was raised in I/R mice. An analysis of HRV and HRT indicated a relative reduction in parasympathetic activity and disturbed baroreflex sensitivity up to 7 days after I/R. In summary, during the first week after I/R, the murine heart reflects essential features of the human heart after myocardial infarction, including a greater vulnerability for VA and a decreased parasympathetic tone accompanied by decelerated depolarization and repolarization parameters.
Comparison of the simulated outcomes of aerosol–cloud interaction by a meteorological model with and without an interactive chemistry module
Authors: Takeishi Azusa , Wang Chien
Published: April 2023

With the general rise of computational capacities and the continued efforts to improve computational efficiencies, more and more studies have been utilizing state-of-the-art atmospheric models that enable cloud-resolving simulations over a global domain. Microphysical processes inside clouds, however, are on a scale much smaller than that of a cloud itself, and therefore resolving clouds in a model is not equivalent to resolving cloud microphysical processes. When aerosol–cloud interaction (ACI) is studied, chemistry models enable the prognostic calculations for chemical species, including aerosols, which can perturb cloud microphysics and eventually impact clouds and climate. The large drawback of these models is the high computational cost required for tracking chemical species in space and time that may not be affordable in some studies. As a result, some studies have used non-chemistry models with prescribed cloud droplet number concentrations $$n_c$$

n
c

and compared multiple simulations with different $$n_c$$

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to assess the impacts of varying aerosol concentrations on clouds. In this study we assess whether the same or similar ACI can be simulated when the aerosol number is increased in a chemistry model and when $$n_c$$

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is raised in a non-chemistry model. A case study has been conducted over the Maritime Continent in September 2015 when an extremely large number of aerosols were observed due to fires under a dry condition brought by a strong El Niño. The comparison of the simulations by the chemistry and non-chemistry models shows that the aerosol-driven enhancement of rainfall in the chemistry simulations was not present in the non-chemistry simulations, even with prescribed $$n_c$$

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with certain spatial variation based on the chemistry runs. Therefore, simulated ACI may largely differ depending on the manner by which an increase or decrease of aerosols is represented in a model. The result suggests the further need for powerful computational capabilities and the pursuit of a rigorous means to incorporate aerosol species in a non-chemistry model.
NSF Fellows’ perceptions about incentives, research misconduct, and scientific integrity in STEM academia
Authors: Roy Siddhartha , Edwards Marc A.
Published: April 2023

There is increased concern about perverse incentives, quantitative performance metrics, and hyper-competition for funding and faculty positions in US academia. Recipients of the prestigious National Science Foundation Graduate Research Fellowships (n = 244) from Civil and Environmental Engineering (45.5%) and Computer Science and Engineering (54.5%) were anonymously surveyed to create a baseline snapshot of their perceptions, behaviors and experiences. NSF Fellows ranked scientific advancement as the top metric for evaluating academics followed by publishing in high-impact journals, social impact of research, and publication/citation counts. The self-reported rate of academic cheating was 16.7% and of research misconduct was 3.7%. Thirty-one percent of fellows reported direct knowledge of graduate peers cheating, and 11.9% had knowledge of research misconduct by colleagues. Only 30.7% said they would report suspected misconduct. A majority of fellows (55.3%) felt that mandatory ethics trainings left them unprepared for dealing with ethical issues. Fellows stated academic freedom, flexible schedules and opportunity to mentor students were the most positive aspects of academia, whereas pressures for funding, publication, and tenure were cited as the most negative aspects. These data may be useful in considering how to better prepare STEM graduate trainees for academic careers.
Unraveling the nature of nano-diamonds and silica in a catheterized tapered artery: highlights into hydrophilic traits
Authors: Abdelsalam Sara I. , Bhatti M. M.
Published: April 2023

In this work, we observe the behavior of a hybrid nanofluidic model containing nanodiamonds and silica nanoparticles. The nanofluid propagates through a catheterized tapered artery with three distinct configurations: converging tapered, non-tapered and diverging tapered arteries. In order to assess the rheological properties of the blood, the third-grade non-Newtonian fluid is employed in the flow model such that the Newtonian versus non-Newtonian effects are revealed. The system of equations governing the flow is modeled under magnetic field and with heat transfer, then solved in a closed form using the perturbation approach for the pertinent parameters. The interpretations of the physical variables of interest, such as the velocity, temperature and wall shear stress, are explained. The integration of diamonds and silica nanoparticles give rise to diverse of biological applications since they are used in the drug delivery and biological imaging in genetic materials due to their hydrophilic surfaces. The present mathematical analysis lays a solid foundation on possible therapeutic applications in biomedicine.