bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fossils Do Not Substantially Improve, and May Even Harm, Estimates of Diversification Rate Heterogeneity
Authors: Beaulieu Jeremy M. , O’Meara Brian C. 
Published: November 2021

AbstractThe fossilized birth-death (FBD) model is a naturally appealing way of directly incorporating fossil information when estimating diversification rates. However, an important yet often overlooked property of the original FBD derivation is that it distinguishes between two types of sampled lineages. Here we first discuss and demonstrate the impact of severely undersampling, and even not including fossils that represent samples of lineages that also had sampled descendants. We then explore the benefits of including fossils, generally, by implementing and then testing two-types of FBD models, including one that converts a fossil set into stratigraphic ranges, in more complex likelihood-based models that assume multiple rate classes across the tree. Under various simulation scenarios, including a scenario that exists far outside the set of models we evaluated, including fossils rarely outperforms analyses that exclude them altogether. At best, the inclusion of fossils improves precision but does not influence bias. Similarly, we found that converting the fossil set to stratigraphic ranges, which is one way to remedy the effects of undercounting the number of k-type fossils, results in turnover rates and extinction fraction estimates that are generally underestimated. While fossils remain essential for understanding diversification through time, in the specific case of understanding diversification given an existing, largely modern tree, they are not especially beneficial.
Tumour mutations in long noncoding RNAs enhance cell fitness
Authors: Esposito Roberta , Lanzós Andrés , Polidori Taisia , Guillen-Ramirez Hugo , Merlin Bernard Mefi , Mela Lia , Zoni Eugenio , Büchi Isabel , Hovhannisyan Lusine , McCluggage Finn , Medo Matúš , Basile Giulia , Meise Dominik F. , Ramnarayanan Sunandini , Zwyssig Sandra , Wenger Corina , Schwarz Kyriakos , Vancura Adrienne , Bosch-Guiteras Núria , Julio Marianna Kruithof-de , Zimmer Yitzhak , Medová Michaela , Stroka Deborah , Fox Archa , Johnson Rory 
Published: November 2021

AbstractLong noncoding RNAs (lncRNAs) can act as tumour suppressors or oncogenes to repress/promote tumour cell proliferation via RNA-dependent mechanisms. Recently, genome sequencing has identified elevated densities of tumour somatic single nucleotide variants (SNVs) in lncRNA genes. However, this has been attributed to phenotypically-neutral “passenger” processes, and the existence of positively-selected fitness-altering “driver” SNVs acting via lncRNAs has not been addressed. We developed and used ExInAtor2, an improved driver-discovery pipeline, to map pancancer and cancer-specific mutated lncRNAs across an extensive cohort of 2583 primary and 3527 metastatic tumours. The 54 resulting lncRNAs are mostly linked to cancer for the first time. Their significance is supported by a range of clinical and genomic evidence, and display oncogenic potential when experimentally expressed in matched tumour models. Our results revealed a striking SNV hotspot in the iconic NEAT1 oncogene, which was ascribed by previous studies to passenger processes. To directly evaluate the functional significance of NEAT1 SNVs, we used in cellulo mutagenesis to introduce tumour-like mutations in the gene and observed a consequent increase in cell proliferation in both transformed and normal backgrounds. Mechanistic analyses revealed that SNVs alter NEAT1 ribonucleoprotein assembly and boost subnuclear paraspeckles. This is the first experimental evidence that mutated lncRNAs can contribute to the pathological fitness of tumour cells.
Brain Networks Detectable by fMRI during On-Line Self Report of Hallucinations in Schizophrenia
Authors: Gill Karanvir , Percival Chantal , Roes Meighen , Arreaza Leo , Chinchani Abhijit , Sanford Nicole , Sena Walter , Mohammadsadeghi Homa , Menon Mahesh , Hughes Matthew , Carruthers Sean , Sumner Philip , Woods Will , Jardri Renaud , Sommer Iris E. , Rossell Susan L. , Woodward Todd S. 
Published: November 2021

SummaryAn analysis of an internationally shared functional magnetic resonance imaging (fMRI) data involving healthy participants and schizophrenia patients extracted brain networks involved in listening to radio speech and capture hallucination experiences. A multidimensional analysis technique demonstrated that for radio-speech sound files, a brain network matching known auditory perception networks emerged, and importantly, displayed speech-duration-dependent hemodynamic responses (HDRs), confirming fMRI detection of these speech events. In the hallucination-capture data, although a sensorimotor (response) network emerged, it did not show hallucination-duration-dependent HDRs. We conclude that although fMRI retrieved the brain network involved in generating the motor responses indicating the start and end of an experienced hallucination, the hallucination event itself was not detected. Previous reports on brain networks detected by fMRI during hallucination capture is reviewed in this context.
OptoAssay – Light-controlled Dynamic Bioassay Using Optogenetic Switches
Authors: Urban Nadine , Hörner Maximillian , Weber Wilfried , Dincer Can 
Published: November 2021

AbstractCircumventing the limitations of current bioassays, we introduce the first light-controlled assay, the OptoAssay, towards wash- and pump-free point-of-care diagnostics. Extending the capabilities of standard bioassays with light-dependent and reversible interaction of optogenetic switches, OptoAssays enable a bi-directional movement of assay components, only by changing the wavelength of light. Combined with smartphones, OptoAssays obviate the need for external flow control systems like pumps or valves and signal readout devices.
Galectin-9 signaling drives breast cancer invasion through matrix
Authors: Pally Dharma , Banerjee Mallar , Hussain Shahid , Kumar Rekha V , Petersson Alexandra , Rosendal Ebba , Gunnarsson Ludvig , Peterson Kristoffer , Leffler Hakon , Nilsson Ulf J. , Bhat Ramray 
Published: November 2021

AbstractAberration in expression and function of glycans and their binding proteins (lectins) in transformed cells constitutes one of the earliest discovered hallmarks of cancer. Galectins are a conserved family of lectins that can bind to β-galactosides. Among them, the role of Galectin-9, a galectin with two carbohydrate binding domains in immune-tumor cell interactions has been well-established, although its effect on cancer cell behavior remains as yet unclear. In this study, we used a spectrum of cell lines from homeostatic breast cells to transformed non-invasive and invasive cell lines cultured in microenvironment-diverse conditions to show that Galectin-9 expression shows an elevation in association with invasiveness of breast cancer epithelia. Our observations were supported by immunohistochemical studies of breast tumors and adjacent normal-tissues from patients. Genetic perturbation of Galectin-9 as well as the pharmacological inhibition of activity using cognate inhibitors confirmed a positive correlation between Galectin-9 levels and the adhesion of the aggressive triple negative breast cancer cells MDA-MB-231 to- and their invasion through-extracellular matrices (ECM). Within a constituted organomimetic multiECM microenvironment, Galectin-9 enhanced both the solitary and the collective invasion of cancer cells. Quantitative proteomics led us to uncover the inductive role of Galectin-9 in the expression of the proinvasive protein S100A4. In addition, Galectin-9 expression correlated with FAK signaling, the inhibition of which decreased S100A4 mRNA levels. Our results provide crucial signaling insights into how the elevation in Galectin-9 expression in breast cancer cells potentiates their invasiveness through ECM during early steps of metastasis.
Cognitive enhancement: Effects of methylphenidate, modafinil and caffeine on latent memory and resting state functional connectivity in healthy adults
Authors: Becker Maxi , Repantis Dimitris , Dresler Martin , Kühn Simone 
Published: November 2021

AbstractStimulants like methylphenidate, modafinil and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebo-controlled study of methylphenidate, modafinil and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the fronto-parietal (FPN) and default mode (DMN) network is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine’s role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g. FPN and DMN) as a potential cognitive enhancement mechanism.
Weak Coupling Between Spontaneous Local Cortical Activity State Switches Under Anesthesia Leads to Strongly Correlated Global Cortical States
Authors: Blackwood Ethan B. , Shortal Brenna P. , Proekt Alex 
Published: November 2021

AbstractUnder anesthesia, neural dynamics deviate dramatically from those seen during wakefulness. During recovery from this perturbation, thalamocortical activity abruptly switches among a small set of metastable intermediate states. These metastable states and structured transitions among them form a scaffold that guides the brain back to the waking state. Here, we investigate the mechanisms that constrain cortical activity to discrete states and give rise to abrupt transitions among them. If state transitions were imposed onto the thalamocortical system by changes in the subcortical modulation, different cortical sites should exhibit near-synchronous state transitions. To test this hypothesis, we quantified state synchrony at different cortical sites in anesthetized rats. States were defined by compressing spectra of layer-specific local field potentials (LFPs) in visual and motor cortices. Transition synchrony, mutual information, and canonical correlations all demonstrate that most state transitions in the cortex are local and that coupling between sites is weak. Fluctuations in the LFP in the thalamic input layer 4 were particularly dissimilar from those in supra- and infra-granular layers. Thus, our results suggest that the discrete global cortical states are not imposed by the ascending modulatory pathways but emerge from the multitude of weak pairwise interactions within the cortex.
The extracellular loops of Salmonella Typhimurium outer membrane protein A (OmpA) maintain the stability of Salmonella containing vacuole (SCV) in murine macrophages and protect the bacteria from autophagy-dependent lysosomal degradation
Authors: Chowdhury Atish Roy , Hajra Dipasree , Chakravortty Dipshikha 
Published: November 2021

AbstractAfter entering the host cells, Salmonella Typhimurium (STM) stays inside a modified membrane-bound compartment called Salmonella containing vacuole (SCV). The biogenesis and stability of SCV are crucial for the intracellular proliferation of Salmonella. Our research has provided a novel mechanistic view on the role of a bacterial porin OmpA in maintaining the stability of SCV. We found that the deletion of OmpA forces the bacteria to escape from the SCV during the immediate early stage of infection. In the absence of OmpA, the bacteria failed to retain the LAMP-1 and came into the host cell’s cytosol. Subsequently, the cytosolic population of STM ΔompA activated the host autophagy machinery after colocalizing with syntaxin 17 and LC3B. The autophagosomes carrying STM ΔompA were targeted to the lysosomes for degradation. Inhibition of autophagy pathway using bafilomycin A1 restored the intracellular proliferation of STM ΔompA. We further showed that the four extracellular loops of OmpA played a crucial role in holding the LAMP-1 pool around the SCV. We have altered the extracellular loop sequences of Salmonella OmpA by site-directed mutagenesis and observed that the bacteria failed to maintain the LAMP-1 pool around the SCV, which finally resulted in their release into the cytosol of the host macrophages. Surprisingly, the cytosolic population of Salmonella having mutations in the extracellular loops of OmpA didn’t activate the lysosomal degradation pathway like STM ΔompA, which helped them to survive within the murine macrophages. In summary, our study revealed an OmpA dependent novel strategy utilized by Salmonella to combat host autophagy by promoting the stability of SCV.
Hypothalamic GABRA5-positive Neurons Control Obesity via Astrocytic GABA
Authors: Sa Moonsun , Yoo Eun-Seon , Koh Wuhyun , Park Mingu Gordon , Jang Hyun-Jun , Yang Yong Ryoul , Lim Jiwoon , Won Woojin , Kwon Jea , Bhalla Mridula , An Heeyoung , Seong Yejin , Lee Seung Eun , Park Ki Duk , Suh Pann-Ghill , Sohn Jong-Woo , Lee C. Justin 
Published: November 2021

SUMMARYThe lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Chemogenetic inhibition of GABRA5LHA suppresses energy expenditure and increases weight gain, whereas gene-silencing of Gabra5 in LHA decreases weight gain. In DIO mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Gene-silencing of astrocytic MAOB in LHA reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a MAOB inhibitor, KDS2010. We propose that firing of GABRA5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.
Do You Want to Build a Genome? Benchmarking Hybrid Bacterial Genome Assembly Methods
Authors: Breckell Georgia L , Silander Olin K 
Published: November 2021

AbstractLong read sequencing technologies now allow routine highly contiguous assembly of bacterial genomes. However, because of the lower accuracy of some long read data, it is often combined with short read data (e.g. Illumina), to improve assembly quality. There are a number of methods available for producing such hybrid assemblies. Here we use Illumina and Oxford Nanopore (ONT) data from 49 natural isolates of Escherichia coli to characterise differences in assembly accuracy for five assembly methods (Canu, Unicycler, Raven, Flye, and Redbean). We evaluate assembly accuracy using five metrics designed to measure structural accuracy and sequence accuracy (indel and substitution frequency). We assess structural accuracy by quantifying (1) the contiguity of chromosomes and plasmids; (2) the fraction of concordantly mapped Illumina reads withheld from the assembly; and (3) whether rRNA operons are correctly oriented. We assess indel and substitution frequency by quantifying (1) the fraction of open reading frames that appear truncated and (2) the number of variants that are called using Illumina reads only. Applying these assembly metrics to a large number of E. coli strains, we find that different assembly methods offer different advantages. In particular, we find that Unicycler assemblies have the highest sequence accuracy in non-repetitive regions, while Flye and Raven tend to be the most structurally accurate. In addition, we find that there are unidentified strain-specific characteristics that affect ONT consensus accuracy, despite individual reads having similar levels of accuracy. The differences in consensus accuracy of the ONT reads can preclude accurate assembly regardless of assembly method. These results provide quantitative insight into the best approaches for hybrid assembly of bacterial genomes and the expected levels of structural and sequence accuracy. They also show that there are intrinsic idiosyncratic strain-level differences that inhibit accurate long read bacterial genome assembly. However, we also show it is possible to diagnose problematic assemblies, even in the absence of ground truth, by comparing long-read first and short-read first assemblies.Author NotesAll supporting data, code and protocols have been provided within the article or through supplementary data files. The supporting code is available from the GitHub repository https://github.com/GeorgiaBreckell/assembly_pipeline. nine supplementary figures and three supplementary tables are available with the online version of this article.Data summarySequence data and genome assemblies for the natural isolates are available at https://www.ebi.ac.uk/ena/browser/view/PRJEB36951. Genome assemblies for additional E. coli strains used here are available from NCBI: (MG1655, SE11, REL606, CFT073, W, IA136, O157:H7-EDL933)
Bayesian Metamodeling of pancreatic islet architecture and functional dynamics
Authors: Lieberman Roee , Mintz Reshef , Raveh Barak 
Published: November 2021

AbstractThe pancreatic islet (islet of Langerhans) is a mini-organ comprising several thousand endocrine cells, functioning jointly to maintain normoglycemia. Cellular networks within an islet were shown to influence its function in health and disease, but there are major gaps in our quantitative understanding of such architecture-function relations. Comprehensive modeling of an islet architecture and function requires the integration of vast amounts of information obtained through different experimental and theoretical approaches. To address this challenge, our lab has recently developed Bayesian metamodeling, a general approach for modeling complex systems by integrating heterogeneous input models. Here, we further developed metamodeling and applied it to construct a metamodel of a pancreatic islet. The metamodel relates islet architecture and function by combining a Monte-Carlo model of architecture trained on islet imaging data; and an ordinary differential equations (ODEs) mathematical model of function trained on calcium imaging, hormone imaging, and electrophysiological data. These input models are converted to a standardized statistical representation relying on Probabilistic Graphical Models; coupled by modeling their mutual relations with the physical world; and finally, harmonized through backpropagation. We validate the metamodel using existing data and use it to derive a testable hypothesis regarding the functional effect of varying intercellular connections. Since metamodeling currently requires substantial expert intervention, we also develop an automation tool for converting models to PGMs (step I) using feedforward neural networks. This automation is a first step towards automating the entire metamodeling process, working towards collaborative science through sharing of expertise, resources, data, and models.
Polygenic and socioeconomic risk for high body mass index: 69 years of follow-up across life
Authors: Bann David , Wright Liam , Hardy Rebecca , Williams Dylan M , Davies Neil M 
Published: November 2021

BackgroundGenetic influences on body mass index (BMI) appear to markedly differ across life, yet existing research is equivocal and limited by a paucity of life course data. Better understanding changes across life in the determinants of BMI may inform etiology, the timing of preventative efforts, and the interpretation of increasing number of studies utilizing genetically-informed designs to study BMI. We thus used a birth cohort study to investigate differences in association and explained variance in the polygenic prediction of BMI from infancy to old age (2-69 years) in a single sample. A secondary aim was to investigate how a key purported environmental influence on BMI (childhood socioeconomic position) differed across life, and whether it operated independently and/or multiplicatively of genetic influences.MethodsData were from up to 2677 participants in the MRC National Survey of Health and Development, with measured weight and height from infancy to old age (12 timepoints from 2-69 years) and genetic data (obtained from blood samples at 53 years). We derived three polygenic indices derived from GWAS of a) adult BMI, b) recalled childhood body size, and c) childhood-adolescence BMI. We investigated associations of each polygenic index and BMI at each age and compared in terms of absolute effect size (β) and explained variance (R2). We used linear and quantile regression models, and finally investigated the additive or multiplicative role of childhood socioeconomic position.ResultsMean BMI and its variance increased across adulthood. For polygenic liability to higher adult BMI (Khera et al), the trajectories of effect size (β) and explained variance (R2) diverged: explained variance peaked in early adulthood and plateaued thereafter, while absolute effect sizes increased throughout adulthood. For polygenic liability to higher childhood BMI, explained variance was largest in adolescence and early adulthood; effect sizes were marginally smaller in absolute terms from adolescence to adulthood. All polygenic indices were related to higher variation in BMI; effect sizes were sizably larger at the upper end of the BMI distribution. Socioeconomic and polygenic risk for higher BMI across life appear to operate additively; we found little evidence of interaction.ConclusionOur findings highlight the likely independent influences of polygenic and socioeconomic factors on BMI across life. Despite sizable associations, the BMI variance explained by each plateaued or declined across adulthood while BMI variance itself increased. This is suggestive of the increasing importance of chance (‘non-shared’) environmental influences on BMI across life.
Transcriptome analysis of Plasmodium falciparum isolates from Benin reveals specific gene expression associated with cerebral malaria
Authors: Guillochon E. , Fraering J. , Joste V. , Kamaliddin C. , Vianou B. , Houzé L. , Baudrin L.G , Faucher J.F. , Aubouy A. , Houzé S. , Cot M. , Argy N. , Taboureau O. , Bertin G.I. ,   NeuroCM group
Published: November 2021

AbstractThe host and parasitic factors leading to cerebral malaria (CM) are not yet fully elucidated and CM Plasmodium falciparum isolates transcriptome profile remains largely unknown. Based on RNA-seq data from 15 CM and 15 uncomplicated malaria (UM) children from Benin, we identified an increased ring stage signature in CM parasites. Reduced circulating time may result from a higher adherence ability of CM isolates and consistent with this hypothesis, we measured an overexpression of var genes in CM. var genes domains expression was more restricted in CM isolates compared to UM, reflecting the specific binding to receptors in host brain endothelium capillaries. However, ICAM-1 binding motif was found expressed in both CM and UM, questioning its role in PfEMP1 adhesion to ICAM-1 receptor. UM isolates increased circulation time may also be modulated by a more efficient immune response against infected erythrocytes surface proteins, which we could not demonstrate on our cohort. Identification of deregulated genes involved in adhesion, excluding variant surface antigens, also supports the hypothesis of an increased CM adhesion capacity. Finally, numerous upregulated genes involved in entry into host pathway were found, reflecting a greater erythrocytes invasion capacity of CM parasites.