bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atherosis of trophoblast type: A specific form of decidual vasculopathy distinct from atherosis of macrophage type
Authors: Zhang Peilin 
Published: July 2021

AbstractBackgroundThere are three types of decidual vasculopathy, namely, acute atherosis, fibrinoid medial necrosis and mural arterial hyerptrophy. Persistence of vascular trophoblasts is also known to be related to maternal vascular malperfusion, but detailed study is lacking.Material and methodsA total 1017 placentas from 2021 were collected with clinical, neonatal and placental information, and routine placental pathology examination was performed. Decidual vasculopathy was classified based on the new classification scheme including atherosis of macrophage type atherosis of trophoblast type, fibrinoid medial necrosis, mural arterial hypertrophy and mixed type vasculopathy. The significance of these morphologic changes were examined based on the clinical, neonatal and placental pathology features.ResultsDecidual vasculopathy is classified as classic type, mural hypertrophy and mixed type. Classic type vasculopathy is further separated as atherosis and fibrinoid medial necrosis. Atherosis is defined as atherosis of macrophage type and atherosis of trophoblast type. Each category of decidual vasculopathy was evaluated in association with maternal, neonatal and placental pathologic findings. Atherosis of macrophage type and mixed type vasculopathy showed statistically significant association with preeclampsia/pregnancy induced hypertension, low birth weight and low placental weight. Atherosis of trophoblast type was associated with lower placental weight but not with specific clinical features. There is no neonatal sex dimorphism in decidual vasculopathy.ConclusionAtherosis of trophoblast type is a distinct pathologic feature in late pregnancy, and it is associated with lower placental weight. New classification of decidual vasculopathy helps with better stratification and categorization of placental maternal vascular abnormalities.
The VersaLive platform enables pipette-compatible microfluidic mammalian cell culture for versatile applications
Authors: Nocera G. M. , Viscido G. , Brillante S. , Carrella S. , di Bernardo D. 
Published: July 2021

AbstractMicrofluidic-based cell culture allows for precise spatio-temporal regulation of microenvironment, live cell imaging and better recapitulation of physiological conditions, while minimizing reagents consumption. Despite their usefulness, most microfluidic systems are designed with one specific application in mind and require specialized equipment and expertise for their operation. All these requirements prevent microfluidic-based cell culture to be widely adopted. Here, we designed and implemented a versatile and easy-to-use perfusion cell culture microfluidic platform for multiple application (VersaLive) requiring only standard pipettes. Here, we showcase the multiple uses of VersaLive (e.g., time-lapse live cell imaging, immunostaining, cell recovery, cell lysis) on mammalian cell lines and primary cells. VersaLive can replace standard cell culture formats in several applications, thus decreasing costs and increasing reproducibility across laboratories. The layout, documentation and protocols are open-source and available online at https://versalive.tigem.it/.
Mammalian UPF3A and UPF3B activate NMD independently of their EJC binding
Authors: Yi Zhongxia , Arvola René M , Myers Sean , Dilsavor Corinne N , Alhasan Rabab Abu , Carter Bayley N , Patton Robert D , Bundschuh Ralf , Singh Guramrit 
Published: July 2021

ABSTRACTNonsense-mediated mRNA decay (NMD) is governed by the three conserved factors - UPF1, UPF2 and UPF3. While all three are required for NMD in yeast, UPF3B is dispensable for NMD in mammals, with its paralog UPF3A suggested to only weakly activate or even repress NMD due to its weaker binding to the exon junction complex (EJC). Here we characterize the UPF3B-dependent and -independent NMD in human cell lines knocked-out of one or bothUPF3paralogs. We show that in human colorectal cancer HCT116 cells, EJC-mediated NMD can operate in UPF3B-dependent and -independent manner. While UPF3A is almost completely dispensable for NMD in wild-type cells, it strongly activates EJC-mediated NMD in cells lacking UPF3B. Surprisingly, this major NMD branch can operate in UPF3-independent manner questioning the idea that UPF3 is needed to bridge UPF proteins to the EJC during NMD. Complementation studies in UPF3 knockout cells further show that EJC-binding domain of UPF3 paralogs is not essential for NMD. Instead, the conserved mid domain of UPF3B, previously shown to engage with ribosome release factors, is required for its full NMD activity. Altogether, UPF3 plays a more active role in NMD than simply being a bridge between the EJC and the UPF complex.
Entorhinal cortex epigenome-wide association study highlights four novel loci showing differential methylation in Alzheimer’s disease
Authors: Sommerer Yasmine , Dobricic Valerija , Schilling Marcel , Ohlei Olena , Sabet Sanaz Sedghpour , Wesse Tanja , Fuß Janina , Franzenburg Sören , Franke Andre , Parkkinen Laura , Lill Christina M. , Bertram Lars 
Published: July 2021

AbstractBackgroundStudies on DNA methylation (DNAm) in Alzheimer’s disease (AD) have recently highlighted several genomic loci showing association with disease onset and progression.MethodsHere, we conducted an epigenome-wide association study (EWAS) using DNAm profiles in entorhinal cortex (EC) from 149 AD patients and control brains and combined these with two previously published EC datasets by meta-analysis (total n=337).ResultsWe identified 12 cytosine-phosphate-guanine (CpG) sites showing epigenome-wide significant association with either case-control status or Braak’s tau-staging. Four of these CpGs, located in proximity toCNFN/LIPE, TENT5A, PALD1/PRF1, andDIRAS1, represent novel findings. Integrating DNAm levels with RNA sequencing-based mRNA expression data generated in the same individuals showed significant DNAm-mRNA correlations for 6 of the 12 significant CpGs. Lastly, by calculating rates of epigenetic age acceleration using two recently proposed “epigenetic clock” estimators we found a significant association with accelerated epigenetic aging in AD patients vs. controls.ConclusionIn summary, our study represents the hitherto most comprehensive EWAS in AD using EC and highlights several novel differentially methylated loci with potential effects on gene expression.
phasebook: haplotype-aware de novo assembly of diploid genomes from long reads
Authors: Luo Xiao , Kang Xiongbin , Schönhuth Alexander 
Published: July 2021

AbstractHaplotype-aware diploid genome assembly is crucial in genomics, precision medicine, and many other disciplines. Long-read sequencing technologies have greatly improved genome assembly thanks to advantages of read length. However, current long-read assemblers usually introduce disturbing biases or fail to capture the haplotype diversity of the diploid genome. Here, we present phasebook, a novel approach for reconstructing the haplotypes of diploid genomes from long reads de novo.Benchmarking experiments demonstrate that our method outperforms other approaches in terms of haplotype coverage by large margins, while preserving competitive performance or even achieving advantages in terms of all other aspects relevant for genome assembly.
RNA modification mapping with JACUSA2
Authors: Piechotta Michael , Wang Qi , Altmüller Janine , Dieterich Christoph 
Published: July 2021

AbstractA whole series of high-throughput antibody-free methods for RNA modification detection from sequencing data emerged lately. We present JACUSA2 as a versatile software solution and comprehensive analysis framework for RNA modification detection assays that are based on either the Illumina or Nanopore platform. Importantly, JACUSA2 can integrate information from multiple experiments (e.g. replicates and different conditions) and different library types (e.g. first- or secondstrand libraries). We demonstrate its utility by example, showing three analysis workflows for m6A detection on published data sets: 1) MazF m6a-sensitive RNA digestion (FTO+ vs FTO-), 2) DART-seq (YTHwt vs YTHmut) and 3) Nanopore profiling (METTL3 +/+ vs -/-). All assays have been conducted in HEK293 cells and complement one another.
Strainline: full-length de novo viral haplotype reconstruction from noisy long reads
Authors: Luo Xiao , Kang Xiongbin , Schönhuth Alexander 
Published: July 2021

AbstractHaplotype-resolved de novo assembly of highly diverse virus genomes is critical in prevention, control and treatment of viral diseases. Current methods either can handle only relatively accurate short read data, or collapse haplotype-specific variations into consensus sequence. Here, we present Strainline, a novel approach to assemble viral haplotypes from noisy long reads without a reference genome. As a crucial consequence, Strainline is the first approach to provide strain-resolved, full-length de novo assemblies of viral quasispecies from noisy third-generation sequencing data. Benchmarking experiments on both simulated and real datasets of varying complexity and diversity confirm this novelty, by demonstrating the superiority of Strainline in terms of relevant criteria in comparison with the state of the art.
mGluR5 Negative Modulators for Fragile X: Resistance and Persistence
Authors: Stoppel David C , McCamphill Patrick K , Senter Rebecca K , Heynen Arnold J , Bear Mark F 
Published: July 2021

AbstractFragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.
Novel canine high-quality metagenome-assembled genomes, prophages, and host-associated plasmids by long-read metagenomics together with Hi-C proximity ligation
Authors: Cuscó Anna , Pérez Daniel , Viñes Joaquim , Fàbregas Norma , Francino Olga 
Published: July 2021

AbstractLong-read metagenomics facilitates the assembly of high-quality metagenome-assembled genomes (HQ MAGs) out of complex microbiomes. It provides highly contiguous assemblies by spanning repetitive regions, complete ribosomal genes, and mobile genetic elements. Hi-C proximity ligation data bins the long contigs and their associated extra-chromosomal elements to their bacterial host. Here, we characterized a canine fecal sample combining a long-read metagenomics assembly with Hi-C data, and further correcting frameshift errors.We retrieved 27 HQ MAGs and seven medium-quality (MQ) MAGs considering MIMAG criteria. All the long-read canine MAGs improved previous short-read MAGs from public datasets regarding contiguity of the assembly, presence, and completeness of the ribosomal operons, and presence of canonical tRNAs. This trend was also observed when comparing to representative genomes from a pure culture (short-read assemblies). Moreover, Hi-C data linked six potential plasmids to their bacterial hosts. Finally, we identified 51 bacteriophages integrated into their bacterial host, providing novel host information for eight viral clusters that included Gut Phage Database viral genomes. Even though three viral clusters were species-specific, most of them presented a broader host range.In conclusion, long-read metagenomics retrieved long contigs harboring complete assembled ribosomal operons, prophages, and other mobile genetic elements. Hi-C binned together the long contigs into HQ and MQ MAGs, some of them representing closely related species. Long-read metagenomics and Hi-C proximity ligation are likely to become a comprehensive approach to HQ MAGs discovery and assignment of extra-chromosomal elements to their bacterial host.
Plasmodium falciparum GBP2 is a telomere-associated protein that binds to G-quadruplex DNA and RNA
Authors: Edwards-Smallbone James , Jensen Anders L. , Roberts Lydia E. , Totanes Francis Isidore G. , Hart Sarah R. , Merrick Catherine J. 
Published: July 2021

SUMMARYIn the early-diverging protozoan parasite Plasmodium, few telomere-binding proteins have been identified and several are unique. Plasmodium telomeres, like those of most eukaryotes, contain guanine-rich repeats that can form G-quadruplex structures. In model systems, quadruplex-binding drugs can disrupt telomere maintenance and some quadruplex-binding drugs are potent anti-plasmodial agents. Therefore, telomere-interacting and quadruplex-interacting proteins may offer new targets for anti-malarial therapy. Here, we report that P. falciparum GBP2 is such a protein. It was identified via ‘Proteomics of Isolated Chromatin fragments’, applied here for the first time in Plasmodium. In vitro, PfGBP2 binds specifically to G-rich telomere repeats in quadruplex form and it can also bind to G-rich RNA. In vivo, PfGBP2 partially colocalises with the known telomeric protein HP1 but is also found in the cytoplasm, probably due to its affinity for RNA. Consistently, its interactome includes numerous RNA-associated proteins. PfGBP2 is evidently a multifunctional DNA/RNA-binding factor in Plasmodium.
Deep learning the arrow of time in brain activity: characterising brain-environment behavioural interactions in health and disease
Authors: Deco Gustavo , Perl Yonatan Sanz , Sitt Jacobo D. , Tagliazucchi Enzo , Kringelbach Morten L. 
Published: July 2021

AbstractThe complex intrinsic and extrinsic forces from the body and environment push the brain into non-equilibrium. The arrow of time, central to thermodynamics in physics, is a hallmark of non-equilibrium and serves to distinguish between reversible and non-reversible dynamics in any system. Here, we use a deep learning Temporal Evolution NETwork (TENET) framework to discover the asymmetry in the flow of events, ‘arrow of time’, in human brain signals, which provides a quantification of how the brain is driven by the interplay of the environment and internal processes. Specifically, we show in large-scale HCP neuroimaging data from a thousand participants that the levels of non-reversibility/non-equilibrium change across time and cognitive state with higher levels during tasks than when resting. The level of non-equilibrium also differentiates brain activity during the seven different cognitive tasks. Furthermore, using the large-scale UCLA neuroimaging dataset of 265 participants, we show that the TENET framework can distinguish with high specificity and sensitivity resting state in control and different neuropsychiatric diseases (schizophrenia, bipolar disorders and ADHD) with higher levels of non-equilibrium found in health. Overall, the present thermodynamics-based machine learning framework provides vital new insights into the fundamental tenets of brain dynamics for orchestrating the interactions between behaviour and brain in complex environments.
An fMRI meta-analysis of the role of the striatum in everyday-life vs laboratory-developed habits
Authors: Guida Pasqualina , Michiels Mario , Redgrave Peter , Luque David , Obeso Ignacio 
Published: July 2021

AbstractThe dorsolateral striatum plays a critical role in the acquisition and expression of stimulus-response habits that are learned in experimental laboratories. Here, we use meta-analytic procedures to contrast the neural circuits activated by laboratory-acquired habits with those activated by stimulus-response behaviours acquired in everyday-life. We confirmed that newly learned habits rely more on the anterior putamen with activation extending into caudate and nucleus accumbens. Motor and associative components of everyday-life habits were identified. We found that motor-dominant stimulus-response associations developed outside the laboratory primarily engaged posterior dorsal putamen, supplementary motor area (SMA) and cerebellum. Importantly, associative components were also represented in the posterior putamen. Thus, common neural representations for both naturalistic and laboratory-based habits were found in the left posterior and right anterior putamen. These findings suggest a partial common striatal substrate for habitual actions that are performed predominantly by stimulus-response associations represented in the posterior striatum. The overlapping neural substrates for laboratory and everyday-life habits supports the use of both methods for the analysis of habitual behaviour.
A Population-level Strain Genotyping Method to Study Pathogen Strain Dynamics in Human Infections
Authors: Morgan Sarah J , Durfey Samantha L , Ravishankar Sumedha , Jorth Peter , Ni Wendy , Skerrett Duncan , Aitken Moira L , Mckone Edward F , Salipante Stephen J , Radey Matthew C , Singh Pradeep K 
Published: July 2021

AbstractA hallmark of chronic bacterial infections is the long-term persistence of one or more pathogen species at the compromised site. Repeated detection of the same bacterial species can suggest that a single strain or lineage is continually present. However, infection with multiple strains of a given species, strain acquisition and loss, and changes in strain relative abundance can occur. Detecting strain-level changes and their effects on disease is challenging as most methods require labor intensive isolate-by-isolate analyses, thus, only a few cells from large infecting populations can be examined. Here we present a population-level method for enumerating and measuring the relative abundance of strains called “PopMLST”. The method exploits PCR amplification of strain-identifying polymorphic loci, next-generation sequencing to measure allelic variants, and informatic methods to determine whether variants arise from sequencing errors or low abundance strains. These features enable PopMLST to simultaneously interrogate hundreds of bacterial cells that are either cultured en masse from patient samples, or are present in DNA directly extracted from clinical specimens without ex vivo culture. This method could be used to detect epidemic or super-infecting strains, facilitate understanding of strain dynamics during chronic infections, and enable studies that link strain changes to clinical outcomes.
Hyperdirect connectivity of opercular speech network to the subthalamic nucleus
Authors: Jorge Ahmed , Lipski Witold J. , Wang Dengyu , Crammond Donald J. , Turner Robert S. , Richardson R. Mark 
Published: July 2021

ABSTRACTThe importance of the basal ganglia in modulating cognitive and motor behaviors is well known, yet how the basal ganglia participate in the uniquely human behavior of speech is poorly understood. The subthalamic nucleus (STN) is well positioned to facilitate two basal ganglia functions critical for speech: motor learning and gain modulation. Using a novel paradigm to study cortical-subcortical interactions during speech in patients undergoing awake DBS surgery, we found evidence for a left opercular hyperdirect pathway in humans by stimulating in the STN and examining antidromic evoked activity in the left temporal, parietal and frontal opercular cortex. These high resolution cortical and subcortical mapping data provided evidence for hyperdirect connectivity between Broca’s area (typically corresponding to pars triangularis and pars opercularis of the inferior frontal gyrus) and the STN. In addition, we observed evoked potentials consistent with the presence of monosynaptic projections from areas of opercular speech cortex that are primarily sensory, including auditory cortex, to the STN. These connections may be unique to humans, evolving alongside the ability for speech.SIGNIFICANCEUsing intracranial recordings from the basal ganglia and cortex in subjects undergoing deep brain stimulation, this study provides evidence for monosynaptic cortical inputs from motor planning, motor sensory, and auditory sensory cortices to the subthalamic nucleus. These observations suggest that in humans, the cortical-basal ganglia hyperdirect pathway is uniquely positioned to participate in speech production. Moreover, the existence of a monosynaptic connection between human sensory cortical areas and the subthalamic nucleus indicates a need to update traditional models of information transfer within cortical-basal ganglia-thalamocortical circuitry, which has significant implications for understanding other human cognitive behavior or dysfunction.
Motif-centric phosphoproteomics to target kinase-mediated signaling pathways
Authors: Tsai Chia-Feng , Ogata Kosuke , Sugiyama Naoyuki , Ishihama Yasushi 
Published: July 2021

SummaryIdentifying cellular phosphorylation pathways based on kinase-substrate relationships is a critical step to understanding the regulation of physiological functions in cells. Mass spectrometry-based phosphoproteomics workflows have made it possible to comprehensively collect information on individual phosphorylation sites in a variety of samples. However, there is still no generic approach to uncover phosphorylation networks based on kinase-substrate relationships in rare cell populations. Here, we describe a motif-centric phosphoproteomics approach combined with multiplexed isobaric labeling, in which in vitro kinase reaction is used to generate the targeted phosphopeptides, which are spiked into one of the isobaric channels to increase detectability. Proof-of-concept experiments demonstrate selective and comprehensive quantification of targeted phosphopeptides by using multiple kinases for motif-centric channels. Over 7,000 tyrosine phosphorylation sites were quantified from several tens of µg of starting materials. This approach enables the quantification of multiple phosphorylation pathways under physiological or pathological regulation in a motif-centric manner.MotivationSensitivity for detecting phosphopeptides with a particular phosphorylation motif is limited, especially for tyrosine phosphopeptides.