bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting nicotinamide N-methyltransferase overcomes resistance to EGFR-TKI in non-small cell lung cancer cells
Authors: Wang Jun , Liu Xi , Huang Yuanfeng , Li Pan , Yang Minqiang , Zeng Shanshan , Chen Danyang , Wang Qian , Liu Hao , Luo Kai , Deng Jin 
Published: April 2022

AbstractActivating mutations of epidermal growth factor receptor (EGFR) contributes to the progression of non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitor (TKI)-targeted therapy has become the standard treatment for NSCLC patients with EGFR-mutations. However, acquired resistance to these agents remains a major obstacle for managing NSCLC. Here, we investigated a novel strategy to overcome EGFR TKI resistance by targeting the nicotinamide N-methyltransferase (NNMT). Using iTRAQ-based quantitative proteomics analysis, we identified that NNMT was significantly increased in EGFR-TKI-resistant NSCLC cells. Moreover, we found that NNMT expression was increased in EGFR-TKI-resistant NSCLC tissue samples, and higher levels were correlated with shorter progression-free survival in EGFR-TKI-treated NSCLC patients. Knockdown of NNMT rendered EGFR-TKI-resistant cells more sensitive to EGFR-TKI, whereas overexpression of NNMT in EGFR-TKI-sensitive cells resulted in EGFR-TKI resistance. Mechanically, upregulation of NNMT increased c-myc expression via SIRT1-mediated c-myc deacetylation, which in turn promoted glycolysis and EGFR-TKI resistance. Furthermore, we demonstrated that the combination of NNMT inhibitor and EGFR-TKI strikingly suppressed the growth of EGFR-TKI-resistant NSCLC cells both in vitro and in vivo. In conclusion, our research indicated that NNMT overexpression is important for acquired resistance to EGFR-TKI and that targeting NNMT might be a potential therapeutic strategy to overcome resistance to EGFR TKI.
Trade-offs in the genetic control of functional and nutritional quality traits in UK winter wheat
Authors: Fradgley Nick S. , Gardner Keith , Kerton Matt , Swarbreck Stéphanie M. , Bentley Alison R. 
Published: April 2022

AbstractA complex network of trade-offs exists between wheat quality and nutritional traits. We investigated the correlated relationships among several milling and baking traits as well as mineral density in refined white and whole grain flour. Our aim was to determine their pleiotropic genetic control in a multi-parent population over two trial years with direct application to practical breeding. Co-location of major quantitative trait loci (QTL) and principal component based multi-trait QTL mapping increased the power to detect QTL and revealed pleiotropic effects explaining many complementary and antagonistic trait relationships. High molecular weight glutenin subunit genes explained much of the heritable variation in important dough rheology traits, although additional QTL were detected. Several QTL, including one linked to the TaGW2 gene, controlled grain size and increased flour extraction rate. The semi-dwarf Rht-D1b allele had a positive effect on Hagberg falling number, but reduced grain size, specific weight, grain protein content and flour water absorption. Mineral nutrient concentrations were lower in Rht-D1b lines for many elements, in wholemeal and white flour, but potassium concentration was higher in Rht-D1b lines. The presence of awns increased calcium content without decreasing extraction rate, despite the negative correlation between these traits. QTL were also found that affect the relative concentrations of key mineral nutrients compared to phosphorus which may help increase bioavailability without associated anti-nutritional effects of phytic acid. Taken together these results demonstrate the potential for marker-based selection to optimise trait trade-offs and enhance wheat nutritional value by considering pleiotropic genetic effects across multiple traits.
A robust and interpretable machine learning approach using multimodal biological data to predict future pathological tau accumulation
Authors: Giorgio Joseph , Jagust William J. , Baker Suzanne , Landau Susan M. , Tino Peter , Kourtzi Zoe ,   Alzheimer’s Disease Neuroimaging Initiative
Published: April 2022

AbstractThe early stages of Alzheimer’s disease (AD) involve interactions between multiple pathophysiological processes. Although these processes are well studied, we still lack robust tools to predict individualised trajectories of disease progression. Here, we employ a robust and interpretable machine learning approach to combine multimodal biological data and predict future pathological tau accumulation. In particular, we use machine learning to quantify interactions between key pathological markers (β-amyloid, medial temporal lobe atrophy, tau and APOE 4) at mildly impaired and asymptomatic stages of AD. Using baseline non-tau markers we derive a prognostic index that: (a) stratifies patients based on future pathological tau accumulation, (b) predicts individualised regional future rate of tau accumulation, and (c) translates predictions from deep phenotyping patient cohorts to cognitively normal individuals. Our results propose a robust approach for fine scale stratification and prognostication with translation impact for clinical trial design targeting the earliest stages of AD.
Modification of BRCA1-associated breast cancer risk by HMMR overexpression
Authors: Mateo Francesca , He Zhengcheng , Mei Lin , de Garibay Gorka Ruiz , Herranz Carmen , García Nadia , Lorentzian Amanda , Baiges Alexandra , Blommaert Eline , Gómez Antonio , Mirallas Oriol , Garrido-Utrilla Anna , Palomero Luis , Espín Roderic , Extremera Ana I. , Soler-Monsó M. Teresa , Petit Anna , Li Rong , Brunet Joan , Chen Ke , Tan Susanna , Eaves Connie J. , McCloskey Curtis , Hakem Razq , Khokha Rama , Lange Philipp F. , Lázaro Conxi , Maxwell Christopher A. , Pujana Miquel Angel 
Published: April 2022

AbstractBreast cancer risk for carriers of BRCA1 pathological variants is modified by genetic factors. Genetic variation in HMMR may contribute to this effect. However, the impact of risk modifiers on cancer biology remains undetermined and the biological basis of increased risk is poorly understood. Here, we depict an interplay of molecular, cellular, and tissue microenvironment alterations that increase BRCA1-associated breast cancer risk. Analysis of genome-wide association results suggests that diverse biological processes, including links to BRCA1-HMMR profiles, influence risk. HMMR overexpression in mouse mammary epithelium increases Brca1-mutant tumorigenesis by modulating the cancer cell phenotype and tumor microenvironment. Elevated HMMR activates AURKA and reduces ARPC2 localization in the mitotic cell cortex, which is correlated with micronucleation and activation of cGAS-STING and non-canonical NF-κB signaling. The initial tumorigenic events are genomic instability, epithelial-to-mesenchymal transition, and tissue infiltration of tumor-associated macrophages. The findings reveal a biological foundation for increased risk of BRCA1-associated breast cancer.
Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19
Authors: Liu Hengrui , Iketani Sho , Zask Arie , Khanizeman Nisha , Bednarova Eva , Forouhar Farhad , Fowler Brandon , Hong Seo Jung , Mohri Hiroshi , Nair Manoj S. , Huang Yaoxing , Tay Nicholas E. S. , Lee Sumin , Karan Charles , Resnick Samuel J. , Quinn Colette , Li Wenjing , Shion Henry , Xia Xin , Daniels Jacob D. , Bartolo-Cruz Michelle , Farina Marcelo , Rajbhandari Presha , Jurtschenko Christopher , Lauber Matthew A. , McDonald Thomas , Stokes Michael E. , Hurst Brett L. , Rovis Tomislav , Chavez Alejandro , Ho David D. , Stockwell Brent R. 
Published: April 2022

AbstractThe SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.
MiDAS 4: A global catalogue of full-length 16S rRNA gene sequences and taxonomy for studies of bacterial communities in wastewater treatment plants
Authors: Dueholm Morten Kam Dahl , Nierychlo Marta , Andersen Kasper Skytte , Rudkjøbing Vibeke , Knutsson Simon ,   MiDAS Global Consortium, Arriaga Sonia , Bakke Rune , Boon Nico , Bux Faizal , Christensson Magnus , Chua Adeline Seak May , Curtis Thomas P. , Cytryn Eddie , Erijman Leonardo , Etchebehere Claudia , Fatta-Kassinos Despo , Frigon Dominic , Garcia-Chaves Maria Carolina , Gu April Z. , Horn Harald , Jenkins David , Kreuzinger Norbert , Kumari Sheena , Lanham Ana , Law Yingyu , Leiknes TorOve , Morgenroth Eberhard , Muszyński Adam , Petrovski Steve , Pijuan Maite , Pillai Suraj Babu , Reis Maria A. M. , Rong Qi , Rossetti Simona , Seviour Robert , Tooker Nick , Vainio Pirjo , van Loosdrecht Mark , Vikraman R. , Wanner Jiří , Weissbrodt David , Wen Xianghua , Zhang Tong , Nielsen Per H. , Albertsen Mads , Nielsen Per Halkjær 
Published: April 2022

AbstractMicrobial communities are responsible for biological wastewater treatment, but our knowledge of their diversity and function is still poor. Here, we sequence more than 5 million high-quality, full-length 16S rRNA gene sequences from 740 wastewater treatment plants (WWTPs) across the world and use the sequences to construct the ‘MiDAS 4’ database. MiDAS 4 is an amplicon sequence variant resolved, full-length 16S rRNA gene reference database with a comprehensive taxonomy from domain to species level for all sequences. We use an independent dataset (269 WWTPs) to show that MiDAS 4, compared to commonly used universal reference databases, provides a better coverage for WWTP bacteria and an improved rate of genus and species level classification. Taking advantage of MiDAS 4, we carry out an amplicon-based, global-scale microbial community profiling of activated sludge plants using two common sets of primers targeting regions of the 16S rRNA gene, revealing how environmental conditions and biogeography shape the activated sludge microbiota. We also identify core and conditionally rare or abundant taxa, encompassing 966 genera and 1530 species that represent approximately 80% and 50% of the accumulated read abundance, respectively. Finally, we show that for well-studied functional guilds, such as nitrifiers or polyphosphate-accumulating organisms, the same genera are prevalent worldwide, with only a few abundant species in each genus.
Asymmetric structure of the native Rhodobacter sphaeroides dimeric LH1–RC complex
Authors: Tani Kazutoshi , Kanno Ryo , Kikuchi Riku , Kawamura Saki , Nagashima Kenji V. P. , Hall Malgorzata , Takahashi Ai , Yu Long-Jiang , Kimura Yukihiro , Madigan Michael T. , Mizoguchi Akira , Humbel Bruno M. , Wang-Otomo Zheng-Yu 
Published: April 2022

AbstractRhodobacter sphaeroides is a model organism in bacterial photosynthesis, and its light-harvesting-reaction center (LH1–RC) complex contains both dimeric and monomeric forms. Here we present cryo-EM structures of the native LH1–RC dimer and an LH1–RC monomer lacking protein-U (ΔU). The native dimer reveals several asymmetric features including the arrangement of its two monomeric components, the structural integrity of protein-U, the overall organization of LH1, and rigidities of the proteins and pigments. PufX plays a critical role in connecting the two monomers in a dimer, with one PufX interacting at its N-terminus with another PufX and an LH1 β-polypeptide in the other monomer. One protein-U was only partially resolved in the dimeric structure, signaling different degrees of disorder in the two monomers. The ΔU LH1–RC monomer was half-moon-shaped and contained 11 α- and 10 β-polypeptides, indicating a critical role for protein-U in controlling the number of αβ-subunits required for dimer assembly and stabilization. These features are discussed in relation to membrane topology and an assembly model proposed for the native dimeric complex.
Introducing principles of synaptic integration in the optimization of deep neural networks
Authors: Dellaferrera Giorgia , Woźniak Stanisław , Indiveri Giacomo , Pantazi Angeliki , Eleftheriou Evangelos 
Published: April 2022

AbstractPlasticity circuits in the brain are known to be influenced by the distribution of the synaptic weights through the mechanisms of synaptic integration and local regulation of synaptic strength. However, the complex interplay of stimulation-dependent plasticity with local learning signals is disregarded by most of the artificial neural network training algorithms devised so far. Here, we propose a novel biologically inspired optimizer for artificial and spiking neural networks that incorporates key principles of synaptic plasticity observed in cortical dendrites: GRAPES (Group Responsibility for Adjusting the Propagation of Error Signals). GRAPES implements a weight-distribution-dependent modulation of the error signal at each node of the network. We show that this biologically inspired mechanism leads to a substantial improvement of the performance of artificial and spiking networks with feedforward, convolutional, and recurrent architectures, it mitigates catastrophic forgetting, and it is optimally suited for dedicated hardware implementations. Overall, our work indicates that reconciling neurophysiology insights with machine intelligence is key to boosting the performance of neural networks.
Collateral sensitivity to pleuromutilins in vancomycin-resistant Enterococcus faecium
Authors: Li Qian , Chen Shang , Zhu Kui , Huang Xiaoluo , Huang Yucheng , Shen Zhangqi , Ding Shuangyang , Gu Danxia , Yang Qiwen , Sun Hongli , Hu Fupin , Wang Hui , Cai Jiachang , Ma Bing , Zhang Rong , Shen Jianzhong 
Published: April 2022

AbstractThe acquisition of resistance to one antibiotic sometimes leads to collateral sensitivity to a second antibiotic. Here, we show that vancomycin resistance in Enterococcus faecium is associated with a remarkable increase in susceptibility to pleuromutilin antibiotics (such as lefamulin), which target the bacterial ribosome. The trade-off between vancomycin and pleuromutilins is mediated by epistasis between the van gene cluster and msrC, encoding an ABC-F protein that protects bacterial ribosomes from antibiotic targeting. In mouse models of vancomycin-resistant E. faecium colonization and septicemia, pleuromutilin treatment reduces colonization and improves survival more effectively than standard therapy (linezolid). Our findings suggest that pleuromutilins may be useful for the treatment of vancomycin-resistant E. faecium infections.
Data-driven discovery of high performance layered van der Waals piezoelectric NbOI2
Authors: Wu Yaze , Abdelwahab Ibrahim , Kwon Ki Chang , Verzhbitskiy Ivan , Wang Lin , Liew Weng Heng , Yao Kui , Eda Goki , Loh Kian Ping , Shen Lei , Quek Su Ying 
Published: April 2022

AbstractUsing high-throughput first-principles calculations to search for layered van der Waals materials with the largest piezoelectric stress coefficients, we discover NbOI2 to be the one among 2940 monolayers screened. The piezoelectric performance of NbOI2 is independent of thickness, and its electromechanical coupling factor of near unity is a hallmark of optimal interconversion between electrical and mechanical energy. Laser scanning vibrometer studies on bulk and few-layer NbOI2 crystals verify their huge piezoelectric responses, which exceed internal references such as In2Se3 and CuInP2S6. Furthermore, we provide insights into the atomic origins of anti-correlated piezoelectric and ferroelectric responses in NbOX2 (X = Cl, Br, I), based on bond covalency and structural distortions in these materials. Our discovery that NbOI2 has the largest piezoelectric stress coefficients among 2D materials calls for the development of NbOI2-based flexible nanoscale piezoelectric devices.
FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice
Authors: Hill Cristal M. , Albarado Diana C. , Coco Lucia G. , Spann Redin A. , Khan Md Shahjalal , Qualls-Creekmore Emily , Burk David H. , Burke Susan J. , Collier J. Jason , Yu Sangho , McDougal David H. , Berthoud Hans-Rudolf , Münzberg Heike , Bartke Andrzej , Morrison Christopher D. 
Published: April 2022

AbstractDietary protein restriction is increasingly recognized as a unique approach to improve metabolic health, and there is increasing interest in the mechanisms underlying this beneficial effect. Recent work indicates that the hormone FGF21 mediates the metabolic effects of protein restriction in young mice. Here we demonstrate that protein restriction increases lifespan, reduces frailty, lowers body weight and adiposity, improves physical performance, improves glucose tolerance, and alters various metabolic markers within the serum, liver, and adipose tissue of wildtype male mice. Conversely, mice lacking FGF21 fail to exhibit metabolic responses to protein restriction in early life, and in later life exhibit early onset of age-related weight loss, reduced physical performance, increased frailty, and reduced lifespan. These data demonstrate that protein restriction in aging male mice exerts marked beneficial effects on lifespan and metabolic health and that a single metabolic hormone, FGF21, is essential for the anti-aging effect of this dietary intervention.
DNA methylation in newborns conceived by assisted reproductive technology
Authors: Håberg Siri E. , Page Christian M. , Lee Yunsung , Nustad Haakon E. , Magnus Maria C. , Haftorn Kristine L. , Carlsen Ellen Ø. , Denault William R. P. , Bohlin Jon , Jugessur Astanand , Magnus Per , Gjessing Håkon K. , Lyle Robert 
Published: April 2022

AbstractAssisted reproductive technology (ART) may affect fetal development through epigenetic mechanisms as the timing of ART procedures coincides with the extensive epigenetic remodeling occurring between fertilization and embryo implantation. However, it is unknown to what extent ART procedures alter the fetal epigenome. Underlying parental characteristics and subfertility may also play a role. Here we identify differences in cord blood DNA methylation, measured using the Illumina EPIC platform, between 962 ART conceived and 983 naturally conceived singleton newborns. We show that ART conceived newborns display widespread differences in DNA methylation, and overall less methylation across the genome. There were 607 genome-wide differentially methylated CpGs. We find differences in 176 known genes, including genes related to growth, neurodevelopment, and other health outcomes that have been associated with ART. Both fresh and frozen embryo transfer show DNA methylation differences. Associations persist after controlling for parents’ DNA methylation, and are not explained by parental subfertility.
Reshuffling of the ancestral core-eudicot genome shaped chromatin topology and epigenetic modification in Panax
Authors: Wang Zhen-Hui , Wang Xin-Feng , Lu Tianyuan , Li Ming-Rui , Jiang Peng , Zhao Jing , Liu Si-Tong , Fu Xue-Qi , Wendel Jonathan F. , Van de Peer Yves , Liu Bao , Li Lin-Feng 
Published: April 2022

AbstractAll extant core-eudicot plants share a common ancestral genome that has experienced cyclic polyploidizations and (re)diploidizations. Reshuffling of the ancestral core-eudicot genome generates abundant genomic diversity, but the role of this diversity in shaping the hierarchical genome architecture, such as chromatin topology and gene expression, remains poorly understood. Here, we assemble chromosome-level genomes of one diploid and three tetraploid Panax species and conduct in-depth comparative genomic and epigenomic analyses. We show that chromosomal interactions within each duplicated ancestral chromosome largely maintain in extant Panax species, albeit experiencing ca. 100–150 million years of evolution from a shared ancestor. Biased genetic fractionation and epigenetic regulation divergence during polyploidization/(re)diploidization processes generate remarkable biochemical diversity of secondary metabolites in the Panax genus. Our study provides a paleo-polyploidization perspective of how reshuffling of the ancestral core-eudicot genome leads to a highly dynamic genome and to the metabolic diversification of extant eudicot plants.
Angular and linear speed cells in the parahippocampal circuits
Authors: Spalla Davide , Treves Alessandro , Boccara Charlotte N. 
Published: April 2022

AbstractAn essential role of the hippocampal region is to integrate information to compute and update representations. How this transpires is highly debated. Many theories hinge on the integration of self-motion signals and the existence of continuous attractor networks (CAN). CAN models hypothesise that neurons coding for navigational correlates – such as position and direction – receive inputs from cells conjunctively coding for position, direction, and self-motion. As yet, very little data exist on such conjunctive coding in the hippocampal region. Here, we report neurons coding for angular and linear velocity, uniformly distributed across the medial entorhinal cortex (MEC), the presubiculum and the parasubiculum, except for MEC layer II. Self-motion neurons often conjunctively encoded position and/or direction, yet lacked a structured organisation. These results offer insights as to how linear/angular speed – derivative in time of position/direction – may allow the updating of spatial representations, possibly uncovering a generalised algorithm to update any representation.
Promoting favorable interfacial properties in lithium-based batteries using chlorine-rich sulfide inorganic solid-state electrolytes
Authors: Zeng Dewu , Yao Jingming , Zhang Long , Xu Ruonan , Wang Shaojie , Yan Xinlin , Yu Chuang , Wang Lin 
Published: April 2022

AbstractThe use of inorganic solid-state electrolytes is considered a viable strategy for developing high-energy Li-based metal batteries. However, suppression of parasitic interfacial reactions and growth of unfavorable Li metal depositions upon cycling are challenging aspects and not yet fully addressed. Here, to better understand these phenomena, we investigate various sulfide inorganic solid electrolytes (SEs), i.e., Li7−xPS6−xClx (x = 0.6, 1.0, 1.3, 1.45, and 1.6), via ex situ and in situ physicochemical and electrochemical measurements. We found that the Cl distribution and the cooling process applied during the SE synthesis strongly influence the evolution of the Li|SE interface in terms of microstructure, interphase composition, and morphology. Indeed, for a SE with a moderate chlorine content (i.e., x = 1.3) and obtained via a slow cooling process after sintering, the Cl atoms are located on the surface of the SE grains as interconnected LiCl nanoparticles that form an extended LiCl-based framework. This peculiar microstructure facilitates the migration of the Cl ions to the Li|SE interface during electrochemical cycling, thus, favouring the formation of a LiCl-rich interphase layer capable of improving the battery cycling performances.