bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hydrodynamic flow and concentration gradients in the gut enhance neutral bacterial diversity
Authors: Labavić Darka , Loverdo Claude , Bitbol Anne-Florence 
Published: May 2021

AbstractThe gut microbiota features important genetic diversity, and the specific spatial features of the gut may shape evolution within this environment. We investigate the fixation probability of neutral bacterial mutants within a minimal model of the gut that includes hydrodynamic flow and resulting gradients of food and bacterial concentrations. We find that this fixation probability is substantially increased compared to an equivalent well-mixed system, in the regime where the profiles of food and bacterial concentration are strongly spatially-dependent. Fixation probability then becomes independent of total population size. We show that our results can be rationalized by introducing an active population, which consists of those bacteria that are actively consuming food and dividing. The active population size yields an effective population size for neutral mutant fixation probability in the gut.Significance statementThe human body harbors numerous and diverse bacteria, the vast majority of which are located in the gut. These bacteria can mutate and evolve within the gut, which is their natural environment. This can have important public health implications, e.g. when gut bacteria evolve antibiotic resistance. The gut features specific characteristics, including hydrodynamic flow and resulting gradients of food and bacterial concentrations. How do these characteristics impact the evolution and diversity of gut bacteria? We demonstrate that they can substantially increase the probability that neutral mutants reach high proportions and eventually take over the population. This is because only a fraction of gut bacteria is actively dividing. Thus, the specific environment of the gut enhances neutral bacterial diversity.
The diversification of Pterocarpus (Leguminosae: Papilionoideae) was influenced by biome-switching and infrequent long-distance dispersal
Authors: Schley Rowan J. , Qin Ming , Vatanparast Mohammad , Malakasi Panagiota , de la Estrella Manuel , Lewis Gwilym , Klitgård Bente 
Published: May 2021

AbstractAimPhenotypes which evolved for dispersal over ecological timescales may lead to significant macroevolutionary consequences, such as infrequent long-distance dispersal and diversification in novel biomes. We aimed to reconstruct the phylogenetic history of Pterocarpus (Leguminosae/ Fabaceae) to assess whether seed dispersal phenotypes and biome switching explain the current biogeographical patterns of this group.LocationPantropicalTaxonThe Pterocarpus clade, particularly Pterocarpus (Leguminosae/Fabaceae)MethodsWe sequenced ~300 nuclear loci captured using Angiosperms-353, a genomic ‘bait set’ for flowering plants, from which we generated a time-calibrated phylogenomic tree. To corroborate this, we also generated a time-calibrated phylogenetic tree from data-mined Sanger-sequencing data. We then collated distribution data and fruit dispersal morphology traits to compare trait-dependent and trait-independent biogeographical models, allowing us to assess whether dispersal traits influenced the spatio-temporal evolution of Pterocarpus. Finally, using the results of these model tests, we estimated the ancestral ranges and biomes of Pterocarpus species to better understand their biogeographical history, and assessed the degree and direction of biome switching over the course of Pterocarpus’ diversification history.ResultsWe recovered well-supported phylogenetic relationships within Pterocarpus, within which there were two subclades – one Neotropical and the other Palaeotropical. Our divergence date estimates suggested that Pterocarpus largely diversified from around 12 Ma, during the Miocene.Trait-dependent biogeographical models were rejected for both range and biome evolution within Pterocarpus, but models parameterising dispersal were supported. Pterocarpus’ ancestral node shared a range across the new-world and old-world tropics, followed by divergence into two clades, one palaeotropical and one neotropical. Biome switching occurred most frequently into rainforest and grassland.Main conclusionsOverall, our analyses suggest that Pterocarpus underwent infrequent cross-continental dispersal and establishment into novel biomes. While this was minimally impacted by fruit dispersal syndromes, biome switching precipitated by long-distance dispersal and environmental change have played an important role in diversification within Pterocarpus since the Miocene.
DynamicRunx1chromatin boundaries affect gene expression in hematopoietic development
Authors: Owens Dominic D.G. , Anselmi Giorgio , Oudelaar A. Marieke , Downes Damien J. , Cavallo Alessandro , Harman Joe R. , Schwessinger Ron , Bucakci Akin , Greder Lucas , de Ornellas Sara , Jeziorska Danuta , Telenius Jelena , Hughes Jim R. , de Bruijn Marella F.T.R. 
Published: May 2021

AbstractThe transcription factor RUNX1 is a critical regulator of developmental hematopoiesis and is frequently disrupted in leukemia.Runx1is a large, complex gene that is expressed from two alternative promoters under the spatiotemporal control of multiple hematopoietic enhancers. To dissect the dynamic regulation ofRunx1in hematopoietic development, we analyzed its three-dimensional chromatin conformation in mouse embryonic stem cell (ESC) differentiation cultures.Runx1resides in a 1.1 Mb topologically associating domain (TAD) demarcated by convergent CTCF motifs. As ESCs differentiate to mesoderm, chromatin accessibility,Runx1enhancer-promoter (E-P) interactions, and CTCF-CTCF interactions increased in the TAD, along with initiation ofRunx1expression from the P2 promoter. Differentiation to hematopoietic progenitor cells was associated with the formation of tissue-specific sub-TADs overRunx1, a shift in E-P interactions, P1 promoter demethylation, and robust expression from bothRunx1promoters. Deletions of promoter-proximal CTCF sites at the sub-TAD boundaries had no obvious effects on E-P interactions but led to partial loss of domain structure, mildly affected gene expression, and delayed hematopoietic development. Together, our analyses of gene regulation at a large multi-promoter developmental gene revealed that dynamic sub-TAD chromatin boundaries play a role in establishing TAD structure and coordinated gene expression.
Intraneuronal chloride levels encode tiredness in cortex
Authors: Alfonsa Hannah , Brodersen Paul , Newey Sarah E. , Yamagata Tomoko , Panayi Marios C. , Bannerman David M. , Vyazovskiy Vladyslav V. , Akerman Colin J. 
Published: May 2021

AbstractContinuous periods of wakefulness are associated with reduced performance levels due to the build-up of sleep pressure in active regions of the brain. These effects manifest as use-dependent changes in cortical network activity and the mechanisms underlying these changes represent targets for overcoming the cognitive effects of tiredness. Here we reveal a central role for intraneuronal chloride levels, which increase in a use-dependent manner during waking, and reduce the strength of local synaptic inhibition in mouse cortex. Activity-dependent increases in chloride account for spatial and temporal features of sleep pressure, they underlie cortical network oscillations in the sleep-deprived state, and targeting chloride regulation in cortex can rescue performance levels when tired. These findings provide a missing link between sleep-wake history, synaptic transmission and cortical dynamics.One-Sentence SummaryThe effects of sleep pressure on cortical function are caused by use-dependent changes in chloride-mediated synaptic inhibition.
Transcriptome analysis reveals higher levels of mobile element-associated abnormal gene transcripts in temporal lobe epilepsy patients
Authors: Hu Kai , Liang Ping 
Published: May 2021

AbstractObjectiveTo determine role of abnormal splice variants associated with mobile elements in epilepsy.MethodsPublicly available human RNA-seq-based transcriptome data for laser-captured dentate granule cells of post-mortem hippocampal tissues from temporal lobe epilepsy patients with (TLE, N=14 for 7 subjects) and without hippocampal sclerosis (TLE-HS, N=8 for 5 subjects) and healthy individuals (N=51), surgically resected bulk neocortex tissues from TLE patients (TLE-NC, N=17). For each individual sample, de novo transcriptome assembly was performed followed by identification of spliced gene transcripts containing mobile element (ME) sequences (ME-transcripts) to compare the ME-transcript frequency across the sample groups. Enrichment analysis for genes associated with ME-transcripts and detailed sequence examination for representative epileptic genes were performed to analyze the pattern and mechanism of ME-transcripts on gene function.ResultsWe observed significantly higher levels of ME-transcripts in the hippocampal tissues of epileptic patients, particularly in TLE-HS. Among ME classes, SINEs were shown to be the most frequent contributor to ME-transcripts followed by LINEs and DNA transposons. These ME sequences almost in all cases represent older MEs normally located in the intron sequences, leading abnormal splicing variants. For protein coding genes, ME sequences were mostly found in the 3’-UTR regions, with a significant portion also in the coding sequences (CDS) leading to reading frame disruption. Genes associated with ME-transcripts showed enrichment for involvement in the mRNA splicing process in all sample groups, with bias towards neural and epilepsy-associated genes in the epileptic transcriptomes.SignificanceOur data suggest that abnormal splicing involving MEs, leading to loss of function in critical genes, plays a role in epilepsy, particularly in TLE-HS, providing a novel insight on the molecular mechanisms underlying epileptogenesis.Key points boxSignificantly higher rates of abnormal splicing variants involving mobile elements (MEs) were observed in the hippocampal tissues of epilepsy patients.SINEs/Alus are most frequently observed in ME-transcripts followed by LINEs and DNA transposons.For protein coding genes, MEs mostly locate in 3’ UTR, but also in coding regions, causing open reading frame disruption, with a bias for neural and epileptic genes.Abnormal splicing involving MEs may be a contributing factor in epileptogenesis.
Non-destructive Chemical Imaging of Bone Tissue for Intraoperative and Diagnostic Applications
Authors: Shin Kseniya S. , Men Shuaiqian , Wong Angel , Cobb-Bruno Colburn , Chen Eleanor , Fu Dan 
Published: May 2021

AbstractBone is difficult to image using traditional histopathological methods, leading to challenges in intraoperative consultations needed in orthopedic oncology. However, intraoperative pathological evaluation is critical in guiding surgical treatment. In this study, we demonstrate that a multimodal imaging approach that combines stimulated Raman scattering (SRS) microscopy, two-photon fluorescence (TPF) microscopy, and second harmonic generation (SHG) microscopy can provide useful diagnostic information regarding intact bone tissue fragments from surgical excision or biopsy specimens. We imaged bone samples from 14 patient cases and performed comprehensive chemical and morphological analyses of both mineral and organic components of bone. Our main findings show that carbonate content combined with morphometric analysis of bone organic matrix can separate several major classes of bone cancer associated diagnostic categories with an average accuracy of >90%. This proof-of-principle study demonstrate that multimodal imaging and machine learning-based analysis of bony tissue can provide crucial diagnostic information for guiding clinical decisions in orthopedic oncology.
The Age-Dependent Decline in Neuron Growth Potential in the CNS is Associated with an Age-Related Dysfunction of Neuronal Mitochondria
Authors: Sutherland Theresa C. , Sefiani Arthur , Horvat Darijana , Huntington Taylor E. , Lei Yuanjiu , West A. Phillip , Geoffroy Cédric G. 
Published: May 2021

AbstractThe age of incidence of Spinal Cord Injury (SCI) and the average age of people living with SCI is continuously increasing. In contrast, SCI is extensively modelled in young adult animals, hampering translation of research to clinical application. While there has been significant progress in manipulating axon growth after injury, how it is impacted by aging impacts this is still unknown. Aging is associated with a decline in mitochondrial functions, whereas mitochondria are essential to successful neurite and axon growth. Using isolation and culture of adult cortical neurons, we have analyzed mitochondrial changes in 2-, 6-, 12- and 18-month mice. We observed reduced neurite growth in older neurons. Older neurons also showed dysfunctional respiration, reduced membrane potential, and altered mitochondrial membrane transport proteins; however mitochondrial DNA (mtDNA) abundance and cellular ATP were increased. Taken together, these data suggest dysfunctional mitochondria in older neurons are involved in the age-dependent reduction in neuron growth. Both normal aging and traumatic injury are associated with mitochondrial dysfunction, posing a challenge for an aging SCI population as the two elements can compound one another to worsen injury outcomes. The results of this study highlight this as an area of great interest in CNS trauma.
Exceptionally high sequence-level variation in the transcriptome ofPlasmodium falciparum
Authors: Dave Bruhad , Kanyal Abhishek , Mamatharani DV , Karmodiya Krishanpal 
Published: May 2021

AbstractSingle-nucleotide variations in RNA (hereafter referred to simply as SNVs), arising from co- and post-transcriptional phenomena including transcription errors and RNA editing, are well studied in organisms ranging from bacteria to humans. In the malaria parasitePlasmodium falciparum, stage-specific and non-specific gene-expression variations are known to accompany the parasite’s array of developmental and morphological phenotypes over the course of its complex life cycle. However, the extent, rate and effect of sequence-level variation in the parasite’s transcriptome are unknown. Here, we report the presence of pervasive, non-specific SNVs in the transcriptome of theP. falciparum. We show that these SNVs cover most of the parasite’s transcriptome. SNV rates for theP. falciparumlines we assayed, as well as for publicly availableP. vivaxandP. falciparumclinical isolate datasets were of the order of 10−3per base, about tenfold higher than rates we calculated for bacterial datasets. These SNVs may reflect an intrinsic transcriptional error rate in the parasite, and RNA editing may be responsible for a subset of them. This seemingly characteristic property of the parasite may have implications for clinical outcomes and the basic biology and evolution ofP. falciparumand parasite biology more broadly, and we anticipate that our study will prompt further investigations into the exact sources, consequences and possible adaptive roles of these SNVs.
Extended interval BNT162b2 vaccination enhances peak antibody generation in older people
Authors: Parry H , Bruton R , Stephens C , Brown K , Amirthalingam G , Hallis B , Otter A , Zuo J , Moss P 
Published: May 2021

AbstractObjectivesTo assess the relative immunogenicity of standard or extended interval BNT162b2 vaccination.DesignPopulation based cohort study comparing immune responses 2 weeks after the second vaccine, with appropriate time-matched samples in participants who received standard or extended interval double vaccination.SettingPrimary care networks, Birmingham, UK. December 2020 to April 2021.Participants172 people aged over 80 years of age. All donors received the BNT162b2 Pfizer/BioNTech vaccination and were vaccinated with either a standard 3 week interval between doses or an extended interval schedule.Main outcome measuresPeak quantitative spike-specific antibody and cellular immune responses.ResultsIn donors without evidence of previous infection the peak antibody response was 3.5-fold higher in donors who had undergone delayed interval vaccination. Cellular immune responses were 3.6-fold lower.ConclusionPeak antibody responses after the second BNT162b2 vaccine are markedly enhanced in older people when this is delayed to 12 weeks although cellular responses are lower. Extended interval vaccination may therefore offer the potential to enhance and extend humoral immunity. Further follow up is now required to assess long term immunity and clinical protection.What is already known on this topicThe BNT162b2 vaccine is highly effective against Covid-19 infection and was delivered with a 3-week time interval in registration studies. However, this interval has been extended in many countries in order to extend population coverage with a single vaccine. It is not known how immune responses after the second dose are influenced by delaying the second vaccine.What this study addsWe provide the first assessment of immune responses in the first 14 weeks after standard or extended interval BNT162b2 vaccination and show that delaying the second dose acts to strongly boost the peak antibody response in older people. The extended interval vaccination may offer a longer period of clinical protection. This information will be of value in optimizing vaccine regimens and help guide guide vaccination policies.
In vivo macromolecular crowding is differentially modulated by Aquaporin 0 in zebrafish lens: insights from a nano-environment sensor and spectral imaging
Authors: Vorontsova Irene , Vallmitjana Alexander , Torrado Belén , Schilling Thomas , Hall James E. , Gratton Enrico , Malacrida Leonel 
Published: May 2021

AbstractMacromolecular crowding is crucial for cellular homeostasis. In vivo studies of macromolecular crowding and ultimately water-dynamics are needed to understand their role in cellular fates. The macromolecular crowding in the lens is essential for understanding normal optics of the lens, and moreover for understanding and prevention of cataract and presbyopia. Here we combine the use of the water nano-environmentally sensitive sensor (6-acetyl-2-dimethylaminonaphthalene, ACDAN) with in vivo studies of Aquaporin zero zebrafish mutants to understand the lens macromolecular crowding. Spectral phasor analysis of ACDAN fluorescence reveal the extent of water dipolar relaxation and demonstrate that the mutations in the duplicated zebrafish Aquaporin 0s, Aqp0a and Aqp0b, alter the water state and macromolecular crowding in the living zebrafish lens. Our results provide in vivo evidence that Aqp0a promotes fluid influx in the deeper lens cortex, whereas Aqp0b facilitates fluid efflux. This work opens new perspectives for in vivo studies on macromolecular crowding.TeaserIn this study we uncover the roles of Aquaporin 0 in macromolecular crowding required for lens development and vision.
Chromosome-scale and haplotype-resolved genome assembly of a tetraploid potato cultivar
Authors: Sun Hequan , Jiao Wen-Biao , Campoy José A. , Krause Kristin , Goel Manish , Folz-Donahue Kat , Kukat Christian , Huettel Bruno , Schneeberger Korbinian 
Published: May 2021

AbstractPotato is the most important tuber crop in the world. However, separate reconstruction of the four haplotypes of its autotetraploid genome remained an unsolved challenge. Here, we report the 3.1 Gb haplotype-resolved (at 99.6% precision), chromosome-scale assembly of the potato cultivar ‘Otava’ using high-quality long reads coupled with single-cell sequencing of 717 pollen genomes and Hi-C data. Unexpectedly, almost 50% of the genome were found to be identical-by-descent due to recent inbreeding, which contrasted by highly abundant structural rearrangements involving around 20% of the genome. Among 38,214 genes, only 54% were present in four haplotypes with an average of 3.2 copies per gene. Analyzing the leaf transcriptome as example, we found that 11% of the genes featured differently expressed alleles in at least one of the haplotypes, of which 25% are likely regulated through allele-specific DNA methylation. Our work sheds light on the recent breeding history of potato, the functional organization of its tetraploid genome and has the potential to strengthen the future of genomics-assisted breeding.
Noncanonical Wnt/Ror2 signaling regulates cell-matrix crosstalk to prompt directional tumor cell invasion and dissemination in breast cancer
Authors: Si Hongjiang , Zhao Na , Pedroza Andrea , Rosen Jeffrey M. , Creighton Chad J. , Roarty Kevin 
Published: May 2021

ABSTRACTBidirectional cell-extracellular matrix (ECM) interactions represent fundamental exchanges during tumor progression. We demonstrate the noncanonical Wnt receptor, Ror2, regulates tumor cell-driven matrix remodeling in models of breast cancer. Wnt/Ror2 loss-of-function triggers tumor cell invasion, accompanied by changes in actin cytoskeleton, adhesion, and collagen crosslinking gene expression programs. E-cadherin levels decline upon Ror2 depletion, and spatially, we pinpoint the upregulation and redistribution of α5 and β3 integrins together with the production of fibronectin in areas of invasion. Wnt/β-catenin-dependent and Wnt/Ror2 alternative Wnt signaling appear to regulate distinct functions for tumor cells regarding their ability to modify cell-ECM exchanges during invasion. Furthermore, blocking either integrin or focal adhesion kinase (FAK), a downstream mediator of integrin-mediated signal transduction, abrogates the enhanced migration observed upon Ror2 loss. These results reveal a critical function for the alternative Wnt receptor, Ror2, as a determinant of reciprocal communication between tumor cells and ECM during cancer invasion and metastasis.
Uncertainty in denoising of MRSI using low-rank methods
Authors: Clarke William T , Chiew Mark 
Published: May 2021

AbstractPurposeLow-rank denoising of MRSI data results in an apparent increase in spectral SNR. However, it is not clear if this translates to a lower uncertainty in metabolite concentrations after spectroscopic fitting. Estimation of the true uncertainty after denoising is desirable for downstream analysis in spectroscopy.In this work the uncertainty reduction from low-rank denoising methods based on spatio-temporal separability and linear predictability in MRSI are assessed. A new method for estimating metabolite concentration uncertainty after denoising is proposed. Finally, automatic rank threshold selection methods are assessed in simulated low SNR regimes.MethodsAssessment of denoising methods is conducted using Monte Carlo simulation of proton MRSI data, and by reproducibility of repeated in vivo acquisitions in five subjects.ResultsIn simulated and in vivo data, spatio-temporal based denoising is shown to reduce the concentration uncertainty, but linear prediction denoising increases uncertainty. Uncertainty estimates provided by fitting algorithms after denoising consistently under-estimate actual metabolite uncertainty. However, the proposed uncertainty estimation, based on an analytical expression for entry-wise variance after denoising, is more accurate. Finally, it is shown automated rank threshold selection using Marchenko-Pastur distribution can bias the data in low SNR conditions. An alternative soft-thresholding function is proposed.ConclusionLow-rank denoising methods based on spatio-temporal separability do reduce uncertainty in MRS(I) data. However, thorough assessment is needed as assessment by SNR measured from residual baseline noise is insufficient given the presence of non-uniform variance. It is also important to select the right rank thresholding method in low SNR cases.