bluuebunny/crossref_metadata_2025_split huggingface dataset:
An initial genomic blueprint of the healthy human oesophageal microbiome
Authors: Gilroy Rachel , Adam Mina E. , Kumar Bhaskar , Pallen Mark J. 
Published: May 2023

Background. The oesophageal microbiome is thought to contribute to the pathogenesis of oesophageal cancer. However, investigations using culture and molecular barcodes have provided only a low-resolution view of this important microbial community. We therefore explored the potential of culturomics and metagenomic binning to generate a catalogue of reference genomes from the healthy human oesophageal microbiome, alongside a comparison set from saliva.
Results. Twenty-two distinct colonial morphotypes from healthy oesophageal samples were genome-sequenced. These fell into twelve species clusters, eleven of which represented previously defined species. Two isolates belonged to a novel species, which we have named Rothia gullae. We performed metagenomic binning of reads generated from UK samples from this study alongside reads generated from Australian samples in a recent study. Metagenomic binning generated 136 medium or high-quality metagenome-assembled genomes (MAGs). MAGs were assigned to 56 species clusters, eight representing novel Candidatus species, which we have named Ca.Granulicatella gullae, Ca. Streptococcus gullae, Ca. Nanosynbacter quadramensis, Ca. Nanosynbacter gullae, Ca.Nanosynbacter colneyensis, Ca. Nanosynbacter norwichensis, Ca. Nanosynococcus oralis and Ca. Haemophilus gullae. Five of these novel species belong to the recently described phylum Patescibacteria. Although members of the Patescibacteria are known to inhabit the oral cavity, this is the first report of their presence in the oesophagus. Eighteen of the metagenomic species were, until recently, identified only by hard-to-remember alphanumeric placeholder designations. Here we illustrate the utility of a set of recently published arbitrary Latinate species names in providing user-friendly taxonomic labels for microbiome analyses.
Our non-redundant species catalogue contained 63 species derived from cultured isolates or MAGs. Mapping revealed that these species account for around half of the sequences in the oesophageal and saliva metagenomes. Although no species was present in all oesophageal samples, 60 species occurred in at least one oesophageal metagenome from either study, with 50 identified in both cohorts.
Conclusions. Recovery of genomes and discovery of new species represents an important step forward in our understanding of the oesophageal microbiome. The genes and genomes that we have released into the public domain will provide a base line for future comparative, mechanistic and intervention studies
Polygenic risk affects the penetrance of monogenic kidney disease
Authors: Khan Atlas , Shang Ning , Nestor Jordan G. , Weng Chunhua , Hripcsak George , Harris Peter C. , Gharavi Ali G. , Kiryluk Krzysztof 
Published: May 2023

ABSTRACTBackgroundChronic kidney disease (CKD) is a genetically complex disease determined by an interplay of monogenic, polygenic, and environmental risks. Most forms of monogenic kidney diseases have incomplete penetrance and variable expressivity. It is presently unknown if some of the variability in penetrance can be attributed to polygenic factors.MethodsUsing the UK Biobank (N=469,835 participants) and the All of Us (N=98,622 participants) datasets, we examined two most common forms of monogenic kidney disorders, autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious variants in thePKD1orPKD2genes, and COL4A-associated nephropathy (COL4A-AN caused by deleterious variants inCOL4A3,COL4A4, orCOL4A5genes). We used the eMERGE-III electronic CKD phenotype to define cases (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or kidney failure) and controls (eGFR >90 mL/min/1.73m2 in the absence of kidney disease diagnoses). The effects of the genome-wide polygenic score (GPS) for CKD were tested in monogenic variant carriers and non-carriers using logistic regression controlling for age, sex, diabetes, and genetic ancestry.ResultsAs expected, the carriers of known pathogenic and rare predicted loss-of-function variants inPKD1orPKD2had a high risk of CKD (ORmeta=17.1, 95% CI: 11.1-26.4, P=1.8E-37). The GPS was comparably predictive of CKD in both ADPKD variant carriers (ORmeta=2.28 per SD, 95%CI: 1.55-3.37, P=2.6E-05) and non-carriers (ORmeta=1.72 per SD, 95% CI=1.69-1.76, P< E-300) independent of age, sex, diabetes, and genetic ancestry. Compared to the middle tertile of the GPS distribution for non-carriers, ADPKD variant carriers in the top tertile had a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile had only a 3-fold increased risk of CKD. Similarly, the GPS was predictive of CKD in both COL4-AN variant carriers (ORmeta=1.78, 95% CI=1.22-2.58, P=2.38E-03) and non-carriers (OR =1.70, 95%CI: 1.68-1.73 P<E-300). The carriers in the top tertile of the GPS had a 2.5-fold higher risk of CKD while the risk for carriers in the bottom tertile was similar to the middle tertile of non-carriers.ConclusionsVariable penetrance of kidney disease in ADPKD and COL4-AN is partially explained by differences in polygenic risk profiles. Accounting for polygenic factors has the potential to improve risk stratification in monogenic kidney disease and may have implications for genetic counseling.
Modeling Protein Structure Using Geometric Vector Field Networks
Authors: Mao Weian , Zhu Muzhi , Chen Hao , Shen Chunhua 
Published: May 2023

AbstractProteins serve as the foundation of life. Most diseases and challenges in life sciences are intimately linked to protein structures. In this paper, we propose a novel vector field network (VFN) for modeling protein structure. Unlike previous methods that extract geometric information relying heavily on hand-crafted features, VFN establishes a new geometric representation paradigm through a novel vector field operator. This vector field operator can not only eliminate the reliance on hand-crafted features, but also capture the implicit geometric relationships between residues. Thus, it enables VFN to have better generalizability and flexibility. We evaluate VFN on the protein inverse folding task. Experiment results show that VFN can significantly improve the performance of the state-of-the-art method, PiFold, by 3.0% (51.7%vs. 54.7%) in terms of the sequence recovery score, and outperform the recent solid baseline, Protein MPNN, by 8.7% (46.0%vs. 54.7%). Furthermore, we scale up VFN with all known protein structure data. Finally, the model achieves a recovery score of57.1%, pushing the accuracy to the next level.
Anaplerotic nutrient stress drives synergy of angiogenesis inhibitors with therapeutics targeting tumor metabolism
Authors: Khadka Sunada , Lin Yu-Hsi , Ackroyd Jeffrey , Chen Yi-An , Sheng Yanghui , Qian Wubin , Guo Sheng , Chen Yining , Behr Eliot , Barekatain Yasaman , Uddin Md. Nasir , Arthur Kenisha , Yan Victoria , Hsu Wen-Hao , Chang Qing , Poral Anton , Tran Theresa , Chaurasia Surendra , Georgiou Dimitra K. , Asara John M. , Barthel Floris P. , Millward Steve W. , DePinho Ronald A. , Muller Florian L. 
Published: May 2023

ABSTRACTTumor angiogenesis is a cancer hallmark, and its therapeutic inhibition has provided meaningful, albeit limited, clinical benefit. While anti-angiogenesis inhibitors deprive the tumor of oxygen and essential nutrients, cancer cells activate metabolic adaptations to diminish therapeutic response. Despite these adaptations, angiogenesis inhibition incurs extensive metabolic stress, prompting us to consider such metabolic stress as aninduced vulnerabilityto therapies targeting cancer metabolism. Metabolomic profiling of angiogenesis-inhibited intracranial xenografts showed universal decrease in tricarboxylic acid cycle intermediates, corroborating a state of anaplerotic nutrient deficit or stress. Accordingly, we show strong synergy between angiogenesis inhibitors (Avastin, Tivozanib) and inhibitors of glycolysis or oxidative phosphorylation through exacerbation of anaplerotic nutrient stress in intracranial orthotopic xenografted gliomas. Our findings were recapitulated in GBM xenografts that do not have genetically predisposed metabolic vulnerabilities at baseline. Thus, our findings cement the central importance of the tricarboxylic acid cycle as the nexus of metabolic vulnerabilities and suggest clinical path hypothesis combining angiogenesis inhibitors with pharmacological cancer interventions targeting tumor metabolism for GBM tumors.
HISTONE DEACETYLASE 19 REGULATESSHOOT MERISTEMLESSEXPRESSION IN THE CARPEL MARGIN MERISTEM CONTRIBUTING TO OVULE NUMBER DETERMINATION AND TRANSMITTING TRACT DIFFERENTIATION
Authors: Manrique S , Cavalleri A , Guazzotti A , Villarino GH , Simonini S , Bombarely A , Higashiyama T , Grossniklaus U , Mizzotti C , Pereira AM , Coimbra S , Sankaranarayanan S , Onelli E , Masiero S , Franks RG , Colombo L 
Published: May 2023

AbstractThe gynoecium is critical for the reproduction of flowering species as it contains the ovules and the tissues required for pollen germination and guidance. These tissues are collectively known as the reproductive tract (ReT) and comprise stigma, style and transmitting tract (TT). The ovules and the ReT originate from a meristem within the pistil named carpel margin meristem (CMM).SHOOT MERISTEMLESS (STM) is a key transcription factor required for meristem formation and maintenance. In all above-ground meristems, including the CMM,STMhas to be locally downregulated to allow proper organ differentiation. However, how this downregulation is achieved in the CMM is unknown.In this work, we have studied HISTONE DEACETYLASE 19 (HDA19) role in ovule and ReT differentiation, based on the observation thathda19-3mutant displays reduced ovule number and fails to properly differentiate the TT. Fluorescence activated cell sorting (FACS) coupled with RNA-seq revealed that in the CMM ofhda19-3mutant, genes promoting organ development are downregulated while meristematic markers, includingSTM, are upregulated. We found that HDA19 is fundamental to downregulateSTMin the CMM, allowing ovule formation and TT differentiation.STMis ectopically expressed inhda19-3at intermediate stages of pistil development, and its downregulation by RNA interference alleviatedhda19-3 phenotypic defects. Furthermore, chromatin immunoprecipitation assays indicated thatSTMis a direct target of HDA19 during pistil development and thatSEEDSTICK(STK)is required for the histone acetylation-mediated regulation ofSTM.Our results have led to the identification of the factors required forSTMsilencing in the gynoecium allowing organogenesis and tissue differentiation from the CMM.
EZH2 inhibition stimulates viral mimicry in resting splenic B cells
Authors: Kim Seung J. , Kiser Patti K. , DeKoter Rodney P. , Dick Frederick A. 
Published: May 2023

SummaryIn mammalian cells expression of repetitive genomic sequences is repressed by heterochromatin, underscoring the potential threat of repeat expression to cellular homeostasis. However, the specific consequences of ectopic repeat expression remains unclear. Here we demonstrate that EZH2 inhibitors stimulate repeat misexpression and cell death in resting splenic B cells. We show that B cells are uniquely sensitive to these agents because of high levels of H3K27me3 at repeats and correspondingly low DNA methylation. We generated a pattern recognition receptor loss-of-function mouse model called RIC with mutations inRigi,Ifih1(MDA5), andCgasto specifically block the consequences of repeat misexpression. In both WT and RIC mutant B cells, EZH2 inhibition caused focused loss of H3K27me3 at repetitive elements and upregulated their expression. However, expression of inflammatory chemokines and cell death were interrupted by the RIC mutations. Furthermore, the chemokine expression patterns induced by EZH2 inhibitors resemble the B cell response to Epstein-Barr virus infection. This study demonstrates a viral mimicry effect induced by pharmacological activation of repeat expression that induces inflammation and B cell death.
Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia
Authors: Weinberger Tobias , Messerer Denise , Joppich Markus , Fischer Max , Garcia Clarisabel , Kumaraswami Konda , Wimmler Vanessa , Ablinger Sonja , Räuber Saskia , Fang Jiahui , Liu Lulu , Liu Wing Han , Winterhalter Julia , Lichti Johannes , Tomas Lukas , Esfandyari Dena , Percin Guelce , Salamanca Sandra Martin , Hidalgo Andres , Waskow Claudia , Engelhardt Stefan , Todica Andrei , Zimmer Ralf , Pridans Clare , Gomez-Perdiguero Elisa , Schulz Christian 
Published: May 2023

ABSTRACTCardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodelling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodelling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodelling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.GRAPHICAL ABSTRACT
Ambulatory electrocardiographic longitudinal monitoring in dystrophin-deficient dogs identifies decreased Very Low Frequency power as a hallmark of impaired Heart Rate Variability in Duchenne Muscular Dystrophy
Authors: Barthélémy Inès , Su Jin Bo , Cauchois Xavier , Relaix Frédéric , Ghaleh Bijan , Blot Stéphane 
Published: May 2023

AbstractBackgroundDuchenne muscular dystrophy (DMD) patients exhibit a late left ventricular systolic dysfunction preceded by an occult phase, during which myocardial fibrosis progresses and some early functional impairments can be detected. These latter include electrocardiographic (ECG) and heart rate variability (HRV) abnormalities.MethodsA longitudinal study aiming at describing the sequence of ECG and HRV abnormalities, relative to cardiac function degradation, using Holter ECG, was performed in the GRMD (Golden retriever muscular dystrophy) dog model, known to develop a DMD-like disease, including cardiomyopathy.ResultsMost of the known ECG and HRV abnormalities described in DMD patients were also found in GRMD dogs, and several of them could be detected months before the decrease of fractional shortening. One of the earliest evidenced abnormalities was a decrease in the very low frequency (VLF) component of the power spectrum, and this decrease was correlated with the further reduction of fractional shortening. Such decreased VLF probably reflects impaired autonomic function and abnormal vasomotor tone.ConclusionThis study provides new insights into the knowledge of the GRMD dog model and DMD cardiomyopathy and emphasizes the interest to monitor the VLF power in DMD patients, still unexplored in this disease, whilst it is highly predictive of deleterious clinical events in many other pathological conditions.AbbreviationscTpnICardiac Troponin IDMDDuchenne Muscular DystrophyECGElectrocardiogramGRMDGolden Retriever Muscular DystrophyHFHigh FrequencyHRHeart RateHRVHeart Rate VariabilityLFLow FrequencyLGELate Gadolinium EnhancementLTVLong-Term VariabilityLVEFLeft Ventricular Ejection FractionNT-proBNPN-Terminal part of the pro-Brain Natriuretic PeptidepNN50percentage of interval differences of successive RR intervals of more than 50 mspNN10 %(meanRR)percentage of interval differences of successive RR intervals of more than 10% of the mean RRQTccorrected QT intervalRMSSDsquare root of the mean squared differences of successive RR intervalsSDNNStandard Deviation of the RR intervalsLVFSLeft Ventricular Fractional ShorteningSTVShort-Term VariabilityVLFVery Low FrequencyPVBPremature Ventricular BeatVTVentricular Tachycardia.
Sprouty4 is required for Mdm2 regulation of invasion, focal adhesion formation and metastasis in cells lacking p53
Authors: Queiroz Rafaela Muniz de , Efe Gizem , Guzman Asja , Hashimoto Naoko , Kawashima Yusuke , Tanaka Tomoaki , Rustgi Anil K , Prives Carol 
Published: May 2023

SummaryAlthough the E3 ligase Mdm2 and its homologue and binding partner MdmX are the major regulators of the p53 tumor suppressor protein, it is now evident that Mdm2 and MdmX have multiple functions that are independent of p53. For example, Mdm2 can regulate cell migration, although mechanistic insight into this function is still lacking. Here we show in cells lacking p53 expression that knockdown of Mdm2 or MdmX, as well as pharmacological inhibition of the Mdm2/MdmX complex, not only reduces cell migration and invasion, but also impairs cell spreading and focal adhesion formation. In addition, Mdm2 knockdown decreases metastasisin vivo. Remarkably, Mdm2 modulates the expression of Sprouty4, which is required for the Mdm2 mediated effects on cell migration, focal adhesion formation and metastasis. Our findings describe a molecular mechanism by which the Mdm2-X complex, through Sprouty4, regulates cellular processes leading to decreased metastatic capability independent of p53.
Toll-like receptor 7 (TLR7)-mediated antiviral response protects mice from lethal SARS-CoV-2 infection
Authors: Ghimire Roshan , Shrestha Rakshya , Amaradhi Radhika , Patton Titus , Whitley Cody , Chanda Debarati , Liu Lin , Ganesh Thota , More Sunil , Channappanavar Rudragouda 
Published: May 2023

ABSTRACTSARS-CoV-2-induced impaired antiviral and excessive inflammatory responses cause fatal pneumonia. However, the key pattern recognition receptors that elicit effective antiviral and lethal inflammatory responsesin-vivoare not well defined. CoVs possess single-stranded RNA (ssRNA) genome that is abundantly produced during infection and stimulates both antiviral interferon (IFN) and inflammatory cytokine/ chemokine responses. Therefore, in this study, using wild-type control and TLR7 deficient BALB/c mice infected with a mouse-adapted SARS-COV-2 (MA-CoV-2), we evaluated the role of TLR7 signaling in MA-CoV-2-induced antiviral and inflammatory responses and disease outcome. We show that TLR7-deficient mice are more susceptible to MA-CoV-2 infection as compared to infected control mice. Further evaluation of MA-CoV-2 infected lungs showed significantly reduced mRNA levels of antiviral type I (IFNα/β) and type III (IFNλ) IFNs, IFN stimulated genes (ISGs, ISG15 and CXCL10), and several pro-inflammatory cytokines/chemokines in TLR7 deficient compared to control mice. Reduced lung IFN/ISG levels and increased morbidity/mortality in TLR7 deficient mice correlated with high lung viral titer. Detailed examination of total cells from MA-CoV-2 infected lungs showed high neutrophil count in TLR7 deficient mice compared to control mice. Additionally, blocking TLR7 activity post-MA-CoV-2 infection using a specific inhibitor also enhanced disease severity. In summary, our results conclusively establish that TLR7 signaling is protective during SARS-CoV-2 infection, and despite robust inflammatory response, TLR7-mediated IFN/ISG responses likely protect the host from lethal disease. Given similar outcomes in control and TLR7 deficient humans and mice, these results show that MA-CoV-2 infected mice serve as excellent model to study COVID-19.
Context dependent function of the transcriptional regulator Rap1 in gene silencing and activation inSaccharomyces cerevisiae
Authors: Bondra Eliana R , Rine Jasper 
Published: May 2023

AbstractInSaccharomyces cerevisiae,heterochromatin is formed through interactions between site-specific DNA-binding factors, including the transcriptional activator Rap1, and Sir proteins. Despite a vast understanding of the establishment and maintenance of Sir-silenced chromatin, the mechanism of gene silencing by Sir proteins has remained a mystery. Utilizing high resolution chromatin immunoprecipitation, we found that Rap1, the native activator of the bi-directionalHMLα promoter, bound its recognition sequence in silenced chromatin and its binding was enhanced by the presence of Sir proteins. In contrast to prior results, various components of transcription machinery were not able to accessHMLα in the silenced state. These findings disproved the long-standing model of indiscriminate steric occlusion by Sir proteins and led to investigation of the transcriptional activator Rap1 in Sir-silenced chromatin. Using a highly sensitive assay that monitors loss-of-silencing events, we identified a novel role for promoter-bound Rap1 in the maintenance of silent chromatin through interactions with the Sir complex. We also found that promoter-bound Rap1 activatedHMLα when in an expressed state, and aided in the transition from transcription initiation to elongation. Highlighting the importance of epigenetic context in transcription factor function, these results point toward a model in which the duality of Rap1 function was mediated by local chromatin environment rather than binding-site availability.Significance StatementThe coarse partitioning of the genome into regions of active euchromatin and repressed heterochromatin is an important, and conserved, level gene expression regulation in eukaryotes. Repressor Activator Protein (Rap1) is a transcription factor that promotes the activation of genes when recruited to promoters, and aids in the establishment of heterochromatin through interactions with silencer elements. Here, we investigate the role of Rap1 when bound to a promoter in silent chromatin and dissect the context-specific epigenetic cues that regulate the dual properties of this transcription factor. Together, our data highlight the importance of protein-protein interactions and local chromatin state on transcription factor function.