bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep Learning Integration of Chest CT Imaging and Gene Expression Identifies Novel Aspects of COPD
Authors: Chen Junxiang , Zhonghui Xu , Sun Li , Yu Ke , Hersh Craig P. , Boueiz Adel , Hokanson John , Sciurba Frank C. , Silverman Edwin K. , Castaldi Peter J. , Batmanghelich Kayhan 
Published: September 2022

AbstractRationaleChronic obstructive pulmonary disease (COPD) is characterized by pathologic changes in the airways, lung parenchyma, and persistent inflammation, but the links between lung structural changes and patterns of systemic inflammation have not been fully described.ObjectivesTo identify novel relationships between lung structural changes measured by chest computed tomography (CT) and systemic inflammation measured by blood RNA sequencing.MethodsCT scan images and blood RNA-seq gene expression from 1,223 subjects in the COPDGene study were jointly analyzed using deep learning to identify shared aspects of inflammation and lung structural changes that we refer to as Image-Expression Axes (IEAs). We related IEAs to COPD-related measurements and prospective health outcomes through regression and Cox proportional hazards models and tested them for biological pathway enrichment.Measurements and Main ResultsWe identified two distinct IEAs: IEAemphcaptures an emphysema-predominant process with a strong positive correlation to CT emphysema and a negative correlation to FEV1and Body Mass Index (BMI); IEAairwaycaptures an airway-predominant process with a positive correlation to BMI and airway wall thickness and a negative correlation to emphysema. Pathway enrichment analysis identified 29 and 13 pathways significantly associated with IEAemphand IEAairway, respectively (adjusted p<0.001).ConclusionsIntegration of CT scans and gene expression data identified two IEAs that capture distinct inflammatory processes associated with emphysema and airway-predominant COPD.At a Glance CommentaryScientific Knowledge on the SubjectChronic obstructive pulmonary disease (COPD) is characterized by lung structural changes and has a prominent systemic inflammatory component, but the links between lung structural changes and patterns of systemic inflammation in COPD have not been fully described.What This Study Adds to the FieldWe identified novel relationships between lung structural changes and systemic inflammation by simultaneously analyzing CT scans and blood RNA-sequencing gene expression using deep learning models. We identified two distinct Image-Expression Axes (IEAs) that characterize different inflammatory processes associated with emphysema and airway predominant COPD.This article has an online data supplement, which is accessible from this issue’s table of content online atwww.atsjournals.org.
WITHDRAWN: A gene expression-based diagnostic classifier for identification of severe COVID-19 and multisystem inflammatory syndrome in children (MIS-C)
Authors: Sotomayor-Gonzalez Alicia , Loy Conor J. , Nguyen Jenny , Servellita Venice , Bhattacharya Sanchita , Lenz Joan , Williams Meagan , Suslovic Will , Cheng Alexandre P. , Bliss Andrew , Saldhi Prachi , Streithorst Jessica , Huh Hee Jae , Foresythe Abiodun , Oseguera Miriam , de la Cruz Katrina , Brazer Noah , Wood Nathan , Hsieh Charlotte , Bahar Burak , Gliwa Amelia , Bhakta Kushmita , Perez Maria A. , Anderson Evan J. , Chahroudi Ann , Delaney Meghan , Butte Atul J. , DeBiasi Roberta , Rostad Christina A. , De Vlaminck Iwijn , Chiu Charles 
Published: September 2022

Withdrawal StatementThe authors have withdrawn their manuscript owing to data from patients who had not been consented being inadvertently used in the preprint. This has been corrected in the version of the study published in Cell Reports Medicine. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Quartet RNA reference materials and ratio-based reference datasets for reliable transcriptomic profiling
Authors: Yu Ying , Hou Wanwan , Wang Haiyan , Dong Lianhua , Liu Yaqing , Sun Shanyue , Yang Jingcheng , Cao Zehui , Zhang Peipei , Zi Yi , Li Zhihui , Liu Ruimei , Gao Jian , Chen Qingwang , Zhang Naixin , Li Jingjing , Ren Luyao , Jiang He , Shang Jun , Zhu Sibo , Wang Xiaolin , Qing Tao , Bao Ding , Li Bingying , Li Bin , Suo Chen , Pi Yan ,   The Quartet Project Team, Wang Xia , Dai Fangping , Scherer Andreas , Mattila Pirkko , Han Jingxiong , Zhang Lijun , Jiang Hui , Thierry-Mieg Danielle , Thierry-Mieg Jean , Xiao Wenming , Hong Huixiao , Tong Weida , Wang Jing , Li Jinming , Fang Xiang , Jin Li , Shi Leming , Xu Joshua , Qian Feng , Zhang Rui , Zheng Yuanting 
Published: September 2022

AbstractAs an indispensable tool for transcriptome-wide analysis of differential gene expression, RNA sequencing (RNAseq) has demonstrated great potential in clinical applications. However, the lack of multi-group RNA reference materials of biological relevance and the corresponding reference datasets for assessing the reliability of RNAseq hampers its wide clinical applications wherein the underlying biological differences among study groups are often small. As part of the Quartet Project for quality control and data integration of multiomic profiling, we established four RNA reference materials derived from immortalized B-lymphoblastoid cell lines from four members of a monozygotic twin family. Additionally, we constructed ratio-based transcriptome-wide reference datasets using multi-batch RNAseq datasets, providing “ground truth” for benchmarking. Moreover, Quartet-sample-based quality metrics were developed for assessing reliability of RNAseq technology in terms of intra-batch proficiency and cross-batch reproducibility. The small intrinsic biological differences among the Quartet samples enable sensitive assessment of performance of transcriptomic measurements. The Quartet RNA reference materials combined with the reference datasets can be served as unique resources for assessing data quality and improving reliability of transcriptomic profiling.
Clinical, socio-demographic, and parental correlates of early autism traits in a community cohort
Authors: Gale-Grant Oliver , Chew Andrew , Falconer Shona , França Lucas G.S , Fenn-Moltu Sunniva , Hadaya Laila , Harper Nicholas , Ciarrusta Judit , Charman Tony , Murphy Declan , Arichi Tomoki , McAlonan Grainne , Nosarti Chiara , Edwards A David , Batalle Dafnis 
Published: September 2022

AbstractBackgroundAutism traits emerge between the ages of 1 and 2. It is not known if experiences which increase the likelihood of childhood autism are related to early trait emergence, or if other exposures are more important. Identifying factors linked to toddler autism traits in the general population may improve our understanding of the mechanisms underlying atypical neurodevelopment.MethodsClinical, socio-demographic, and parental information was collected at birth from 536 toddlers in London, UK (gestational age at birth, sex, maternal body mass index, age, parental education level, parental first language, parental history of neurodevelopmental disorders) and at 18 months (parent cohabiting status, two measures of social deprivation, three measures of maternal parenting style, and a measure of maternal postnatal depression). General neurodevelopment was assessed with the Bayley Scales of Infant and Toddler Development, 3rdEdition (BSID-III), and autism traits were assessed using the Quantitative Checklist for Autism in Toddlers (Q-CHAT). Multivariable models were used to identify associations between variables and Q-CHAT. A model including BSID-III was used to identify factors associated with Q-CHAT independent of general neurodevelopment. Models were also evaluated addressing variable collinearity with principal component analysis (PCA).ResultsA multivariable model explained 20% of Q-CHAT variance, with four individually significant variables (two measures of parenting style and two measures of socio-economic deprivation). After adding general neurodevelopment into the model 36% of Q-CHAT variance was explained, with three individually significant variables (two measures of parenting style and one measure of language development). After addressing variable collinearity with PCA, parenting style and social deprivation were positively correlated with Q-CHAT score via a single principal component, independently of general neurodevelopment. Neither sex nor family history of autism were associated with Q-CHAT score.LimitationsThe Q-CHAT is parent rated and is therefore a subjective opinion rather than a clinical assessment. We measured Q-CHAT at a single timepoint, and to date no participant has been followed up in later childhood, so we are focused purely on emerging traits rather than clinical autism diagnoses.ConclusionsAutism traits are common at age 18 months, and greater emergence is specifically related to exposure to early life adversity.
Investigating the ability of astrocytes to drive neural network synchrony
Authors: Handy Gregory , Borisyuk Alla 
Published: September 2022

AbstractRecent experimental works have implicated astrocytes as a significant cell type underlying several neuronal processes in the mammalian brain, from encoding sensory information to neurological disorders. Despite this progress, it is still unclear how astrocytes are communicating with and driving their neuronal neighbors. While previous computational modeling works have helped propose mechanisms responsible for driving these interactions, they have primarily focused on interactions at the synaptic level, with microscale models of calcium dynamics and neurotransmitter diffusion. Since it is computationally infeasible to include the intricate microscale details in a network-scale model, little computational work has been done to understand how astrocytes may be influencing spiking patterns and synchronization of large networks. We overcome this issue by first developing an “effective” astrocyte that can be easily implemented to already established network frameworks. We do this by showing that the astrocyte proximity to a synapse makes synaptic transmission faster, weaker, and less reliable. Thus, our “effective” astrocytes can be incorporated by considering heterogeneous synaptic time constants, which are parametrized only by the degree of astrocytic proximity at that synapse. We then apply our framework to large networks of exponential integrate-and-fire neurons with various spatial structures. Depending on key parameters, such as the number of synapses ensheathed and the strength of this ensheathment, we show that astrocytes can push the network to a synchronous state and exhibit spatially correlated patterns.Author summaryIn many areas of the brain, glial cells called astrocytes wrap their processes around synapses – the points of contact between neurons. The number of wrapped synapses and the tightness of wrapping varies between brain areas and changes during some diseases, such as epilepsy. We investigate the effect that this synaptic ensheathment has on communication between neurons and the resulting collective dynamics of the neuronal network. We present a general, computationally-efficient way to include astrocytes in neuronal networks using an “effective astrocyte” representation derived from detailed microscopic scale models. The resulting hybrid networks allow us to emulate and observe the effect of ensheathment conditions corresponding to different brain areas and disease states. In particular, we find that it makes the networks more likely to switch into a highly correlated regime, contrary to predictions from the traditional neurons-only view. These results open a new perspective on neural network dynamics, where our understanding of conditions for generating correlated brain activity (e.g., rhythms associated with various brain functions, epileptic seizures) needs to be reevaluated.
Engineering Alignment has Mixed Effects on hiPSC-CM Maturation
Authors: Kalkunte Nikhith G. , Delabmbre Talia E , Sohn Sogu , Pickett Madison , Parekh Sapun , Zoldan Janet 
Published: September 2022

AbstractThe potential of human induced pluripotent stem cell differentiated cardiomyocytes (hiPSC-CMs) is greatly limited by their functional immaturity. Strong relationships exist between CM structure and function, leading many in the field to seek ways to mature hiPSC-CMs by culturing on biomimetic substrates, specifically those that promote alignment. However, these in vitro models have so far failed to replicate the alignment that occurs during cardiac differentiation. We show that engineered alignment, incorporated before and during cardiac differentiation, affects hiPSC-CM electrochemical coupling and mitochondrial morphology. We successfully engineer alignment in differentiating hiPSCs as early as Day 4. We uniquely apply optical redox imaging to monitor the metabolic changes occurring during cardiac differentiation. We couple this modality with cardiac-specific markers, which allows us to assess cardiac metabolism in heterogeneous cell populations. The engineered alignment drives hiPSC-CM differentiation towards the ventricular compact CM subtype and improves electrochemical coupling in the short term. Moreover, we observe glycolysis to oxidative phosphorylation switch throughout differentiation and CM development. On the subcellular scale, we note changes in mitochondrial morphology in the long term. Our results demonstrate that cellular alignment accelerates hiPSC-CM maturity and emphasizes the interrelation of structure and function in cardiac development. We anticipate that combining engineered alignment with additional maturation strategies will result in improved development of mature CMs from hiPSC and strongly improve cardiac tissue engineering.Impact StatementThis work demonstrates the mixed effect of engineered structure in inducing matured function of human induced pluripotent stem cell -derived cardiomyocytes. Isolating the impacts of hiPSC-CM alignment on functionality is a necessary step in optimizing the culture conditions to develop cardiac cell therapies. Furthermore, our work has broader implications concerning how we understand the impact of mechanical microenvironments on stem cell differentiation and development.
Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system
Authors: Frank Michelle M. , Sitko Austen A. , Suthakar Kirupa , Torres Cadenas Lester , Hunt Mackenzie , Yuk Mary Caroline , Weisz Catherine J.C. , Goodrich Lisa V. 
Published: September 2022

SUMMARYBrainstem olivocochlear neurons (OCNs) modulate the earliest stages of auditory processing through feedback projections to the cochlea and have been shown to influence hearing and protect the ear from sound-induced damage through unclear mechanisms. Here, we used single-nucleus sequencing, anatomical reconstructions, and electrophysiology to characterize OCNs during postnatal development and after sound exposure. We identified markers for known OCN subtypes, medial (MOC) and lateral (LOC) OCNs, and show that they express distinct cohorts of physiologically relevant genes that change over development. In addition, we discovered a neuropeptide-enriched LOC subtype that produces Neuropeptide Y along with other neurotransmitters. Throughout the cochlea, both LOC subtypes extend arborizations over wide frequency domains. Moreover, LOC neuropeptide expression is strongly upregulated days after acoustic trauma, potentially providing a sustained protective signal to the cochlea. OCNs are therefore poised to have diffuse, dynamic effects on early auditory processing over timescales ranging from milliseconds to days.
Substrate-binding Glycine Residues are Major Determinants for Hydrolase and Ligase Activity of Plant Legumains
Authors: Hemu Xinya , Chan Ning-Yu , Liew Heng Tai , Hu Side , Zhang Xiaohong , Serra Aida , Lescar Julien , Liu Chuan-Fa , Tam James P 
Published: September 2022

ABSTRACTPeptide asparaginyl ligases (PALs) are Asn/Asp(Asx)-specific ligases that are useful for precision modifications of proteins and live-cell surfaces. However, PALs share high structural similarity to the far more common asparaginyl endopeptidases (AEPs), also known as legumains that hydrolyze peptide bonds after Asx, thus making it challenging to identify PALs in a sea of AEPs. Previously we identified sequences flanking the catalytic site as ligase activity determinants (LADs) for legumains. Here we show that two conserved substrate-binding Gly residues are critical, but negative determinants for ligase activity, based on a combined bioinformatics analysis of 1,500 plant legumains, mutagenesis and functional study of 16 novel legumains, plus identification of seven new PALs. We also show that PALs are rare and AEPs are much more common, accounting for about 1% and 88%, respectively. Our results suggest that specific glycine residues are molecular determinants to identify PALs and AEPs as two different legumain subfamilies.
Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS/AML
Authors: Wheeler Emily C , Martin Benjamin J E , Doyle William C , Gorelov Rebecca A , Donahue Melanie , Jann Johann C , Abdel-Wahab Omar , Taylor Justin , Seiler Michael , Buonamici Silvia , Belizaire Roger , Adelman Karen , Tothova Zuzana 
Published: September 2022

AbstractSplicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer, including myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they are associated with poor outcomes. Here, we show that cohesin mutations are biomarkers of sensitivity to drugs targeting the splicing-factor SF3B1 (H3B-8800 and E-7107). We identify drug-induced alterations in splicing and corresponding reduced gene expression of a large number of DNA repair genes, including BRCA1 and BRCA2, as the mechanism underlying this sensitivity in cell line models, primary patient samples and patient-derived xenograft (PDX) models of AML. We find that DNA damage repair genes are particularly sensitive to exon skipping induced by SF3B1 modulators given their long length and large number of exons per transcript. Furthermore, we demonstrate that treatment of cohesin-mutant cells with SF3B1 modulators not only results in impaired DNA damage response and accumulation of DNA damage, but it significantly sensitizes cells to subsequent killing by PARP inhibitors and chemotherapy, and leads to improved overall survival of PDX models of cohesin-mutant AML in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS and AML, and we propose this as a broader strategy for therapeutic targeting of other DNA damage-repair deficient cancers.One Sentence SummaryWe identify an unexpected effect of SF3B1 splicing inhibitors on regulation of DNA damage repair genes and show efficacy of combination treatment in cohesin-mutant MDS and AML.
Programming super DNA-enzyme molecules for on-demand enzyme activity modulation
Authors: Zhao Haipei , Xiu Xuehao , Li Mingqiang , Gou Mingyang , Tao Leyang , Zuo Xiaolei , Fan Chunhai , Tian Zhongqun , Song Ping 
Published: September 2022

AbstractDynamic interactions of enzymes, including programmable configuration and cycling of enzymes, play important roles in the regulation of cellular metabolism. Here, we construct a super DNA-enzymes molecule (SDEM) that comprises at least two cascade enzymes and linked DNA strands to control and detect metabolism. We find that the programmable SDEM which comprises glucose oxidase (GOx) and horseradish peroxidase (HRP) has a 50-fold lower detection of limit and a 1.6-fold higher reaction rate than free enzymes. SDEM can be assembled and disassembled using a hairpin structure and a displacement DNA strand to complete multiple cycles. An entropically driven catalytic assembly (catassembly) enables different SDEMs to switch from SDEM with GOx and HRP cascades to SDEM with sarcosine oxidase (SOX) and HRP cascades by over six orders of magnitude less time than no catassembly to detect different metabolisms (glucose and sarcosine) on demand.
In vitro synergistic action of TAT-RasGAP317-326 peptide with antibiotics against Gram-negative pathogens
Authors: Vizzarro Grazia , Jacquier Nicolas 
Published: September 2022

AbstractObjectivesMultidrug-resistant (MDR) bacteria are a continuously increasing threat for medicine, causing infections recalcitrant to antibiotics. Antimicrobial peptides (AMPs) were identified as alternatives to antibiotics, being naturally occurring short peptides and part of the innate immune system of a vast majority of organisms. However, the clinical application of AMPs is limited by suboptimal pharmacokinetic properties and relatively high toxicity. Combinatorial treatments using AMPs and classical antibiotics may decrease the concentrations of AMPs required for bacterial eradication, thus lowering the side effects of these peptides.MethodsHere, we investigate the in vitro efficiency of combinations of the recently described antimicrobial peptide TAT-RasGAP317-326 with a panel of commonly used antimicrobial agents against three Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii using checkerboard and time-kill assays.ResultsWe identified synergistic combinations towards all three bacteria and demonstrated that these combinations had an increased bactericidal effect compared to individual drugs. Moreover, combinations were also effective against clinical isolates of A. baumannii. Finally, combination of TAT-RasGAP317-326 and meropenem had a promising antibiofilm effect towards A. baumannii.ConclusionTaken together, our results indicate that combinations of TAT-RasGAP317-326 with commonly-used antimicrobial agents may lead to the development of new treatment protocols against infections caused by MDR bacteria.
The population-level impact of Enterococcus faecalis genetics on intestinal colonisation and extraintestinal infection
Authors: Chaguza Chrispin , Pöntinen Anna K. , Top Janetta , Arredondo-Alonso Sergio , Freitas Ana R. , Novais Carla , Torres Carmen , Bentley Stephen D. , Peixe Luisa , Coque Teresa M. , Willems Rob J.L. , Corander Jukka 
Published: September 2022

AbstractEnterococcus faecalis is a commensal pathogenic bacterium commonly found in the human gastrointestinal tract and a cause of opportunistic infections typically associated with multidrug resistance. The E. faecalis genetic changes associated with pathogenicity and extraintestinal infection, particularly through gut-to-bloodstream translocation, are poorly understood. Here, we investigate the E. faecalis genetic signatures associated with intestinal colonisation and extraintestinal infection and infection of hospitalised and non-hospitalised individuals using heritability estimation and a genome-wide association study (GWAS). We analysed 750 whole-genome sequences of faecal and bloodstream E. faecalis isolates from hospitalised patients and non-hospitalised individuals, respectively, predominantly in Europe. We found that E. faecalis infection of individuals depending on their hospitalisation status and extraintestinal infection are heritable traits and that ∼24% and ∼34% of their variation is explained by the considered genetic effects, respectively. Further, a GWAS using linear mixed models did not pinpoint any clear enrichment of individual genetic changes in isolates from different isolation sites and individuals with varying hospitalisation statuses, suggesting that these traits are highly polygenic. Altogether, our findings indicate that E. faecalis infection and extraintestinal infection are influenced by variation in genetic, host, and environmental factors, and ultimately the opportunistic pathogenic lifestyle of this versatile host generalist bacterium.