bluuebunny/crossref_metadata_2025_split huggingface dataset:
BigBrainWarp: Toolbox for integration of BigBrain 3D histology with multimodal neuroimaging
Authors: Paquola Casey , Royer Jessica , Lewis Lindsay B. , Lepage Claude , Glatard Tristan , Wagstyl Konrad , DeKraker Jordan , Toussaint Paule-J , Valk Sofie L , Collins Louis , Khan Ali R. , Amunts Katrin , Evans Alan C. , Dickscheid Timo , Bernhardt Boris 
Published: May 2021

AbstractNeuroimaging stands to benefit from emerging ultrahigh-resolution histological atlases of the human brain; the first of which is “BigBrain”. Ongoing research aims to characterise regional differentiation of cytoarchitecture with BigBrain and to optimise registration of BigBrain with standard neuroimaging templates. Together, this work paves the way for multi-scale investigations of brain organisation. However, working with BigBrain can present new challenges for neuroimagers, including dealing with cellular resolution neuroanatomy and complex transformation procedures. To simplify workflows and support adoption of best practices, we developed BigBrainWarp, a toolbox for integration of BigBrain with multimodal neuroimaging. The primary BigBrainWarp function wraps multiple state-of-the-art deformation matrices into one line of code, allowing users to easily map data between BigBrain and standard MRI spaces. Additionally, the toolbox contains ready-to-use cytoarchitectural features to improve accessibility of histological information. The present article discusses recent contributions to BigBrain-MRI integration and demonstrates the utility of BigBrainWarp for further investigations.
Characterization of the ABC methionine transporter fromNeisseria meningitidisreveals that MetQ is a lipoprotein
Authors: Sharaf Naima G. , Shahgholi Mona , Kim Esther , Lai Jeffrey Y. , VanderVelde David , Lee Allen T. , Rees Douglas C. 
Published: May 2021

AbstractNmMetQ is a substrate binding protein (SBP) fromNeisseria meningitidisthat has been identified as a surface-exposed candidate antigen for meningococcal vaccines. However, this location for NmMetQ challenges the prevailing view that SBPs in Gram-negative bacteria are localized to the periplasmic space to promote interaction with their cognate ABC transporter embedded in the bacterial inner membrane. To address the roles of NmMetQ, we characterized NmMetQ with and without its cognate ABC transporter (NmMetNI). Here, we show that NmMetQ is a lipoprotein (lipo-NmMetQ) that binds multiple methionine analogs and stimulates the ATPase activity of NmMetNI. Using single-particle electron cryo-microscopy, we determined the structures of NmMetNI in the absence and presence of lipo-NmMetQ. Based on our data, we propose that NmMetQ tethers to membranes via a lipid anchor and has dual function/topology, playing a role in NmMetNI-mediated transport at the inner-membrane in addition to moonlighting functions on the bacterial surface.
Cortical Surface-Informed Volumetric Spatial Smoothing of fMRI Data via Graph Signal Processing
Authors: Behjat Hamid , Westin Carl-Fredrik , Aganj Iman 
Published: May 2021

AbstractConventionally, as a preprocessing step, functional MRI (fMRI) data are spatially smoothed before further analysis, be it for activation mapping on task-based fMRI or functional connectivity analysis on resting-state fMRI data. When images are smoothed volumetrically, however, isotropic Gaussian kernels are generally used, which do not adapt to the underlying brain structure. Alternatively, cortical surface smoothing procedures provide the benefit of adapting the smoothing process to the underlying morphology, but require projecting volumetric data on to the surface. In this paper, leveraging principles from graph signal processing, we propose avolumetricspatial smoothing method that takes advantage of the gray-white and pial cortical surfaces, and as such, adapts the filtering process to the underlying morphological details at each point in the cortex.
Comprehensive PAM prediction for CRISPR-Cas systems reveals evidence for spacer sharing, preferred strand targeting and conserved links with CRISPR repeats
Authors: Vink Jochem NA , Baijens Jan HL , Brouns Stan JJ 
Published: May 2021

AbstractThe adaptive CRISPR-Cas immune system stores sequences from past invaders as spacers in CRISPR arrays and thereby provides direct evidence that links invaders to hosts. Mapping CRISPR spacers has revealed many aspects of CRISPR biology, including target requirements such as the protospacer adjacent motif (PAM). However, studies have so far been limited by a low number of mapped spacers in the database. By using vast metagenomic sequence databases, we mapped one third (∼70,000) of more than 200,000 unique CRISPR spacers from a variety of microbes, and derived a catalog of more than one hundred unique PAM sequences associated with specific CRISPR subtypes. These PAMs were further used to correctly assign the orientation of CRISPR arrays, revealing conserved patterns between the last nucleotides of the CRISPR repeat and PAM. From the curated CRISPR arrays dataset we could also deduce CRISPR subtype specific preferences for targeting either template or coding strand of open reading frames. While some DNA-targeting systems (e.g. Type I-E and Type II systems) prefer the template strand and avoid mRNA, other DNA- and RNA-targeting systems (i.e. Type I-A, I-B and Type III systems) prefer the coding strand and mRNA. In addition, we found large scale evidence that both CRISPR adaptation machinery and CRISPR arrays are shared between different CRISPR-Cas systems. This could lead to simultaneous DNA- and RNA targeting of invaders, which may be effective at combating mobile genetic invaders.
Increased mitochondrial activity upon CatSper channel activation is required for sperm capacitation
Authors: Ferreira Juan J. , Cassina Adriana , Irigoyen Pilar , Ford Mariana , Pietroroia Santiago , Radi Rafael , Santi Celia M. , Sapiro Rossana 
Published: May 2021

AbstractTo fertilize an oocyte, sperm must become hyperactive. However, whether they obtain ATP for hyperactivated motility via glycolysis or mitochondrial respiration is unclear. Here, high-resolution respirometry, flow cytometry, and confocal microscopy experiments revealed that mitochondrial respiration and membrane potential increased during mouse sperm capacitation. Treatment with inhibitors of mitochondrial respiration prevented sperm from hyperactivating and fertilizing an oocyte. Mitochondrial respiration was impaired in sperm from mice lacking the calcium channel CatSper. We developed a method to image mitochondrial calcium in sperm and found that CatSper activation led to increased mitochondrial calcium concentration. Finally, treating sperm with an inhibitor of mitochondrial calcium import impaired mitochondrial function and sperm hyperactivation. Together, our results uncover a new role of sperm mitochondria and reveal a new pathway connecting calcium influx through CatSper to mitochondrial activity and the sperm hyperactivation required to fertilize an oocyte.SummaryThe source of ATP for sperm hyperactivation is unclear. Ferreira et al. show that mitochondrial activity increases during, and is required for, hyperactivation and fertilization ability. Increased mitochondrial activity depends on calcium influx through the channel CatSper.
Evolution of enzyme levels in metabolic pathways: A theoretical approach
Authors: Coton Charlotte , Talbot Grégoire , Le Louarn Maud , Dillmann Christine , de Vienne Dominique 
Published: May 2021

AbstractThe central role of metabolism in cell functioning and adaptation has given rise to count-less studies on the evolution of enzyme-coding genes and network topology. However, very few studies have addressed the question of how enzyme concentrations change in response to positive selective pressure on the flux, considered a proxy of fitness. In particular, the way cellular constraints, such as resource limitations and co-regulation, affect the adaptive landscape of a pathway under selection has never been analyzed theoretically. To fill this gap, we developed a model of the evolution of enzyme concentrations that combines metabolic control theory and an adaptive dynamics approach, and integrates possible dependencies between enzyme concentrations. We determined the evolutionary equilibria of enzyme concentrations and their range of neutral variation, and showed that they differ with the properties of the enzymes, the constraints applied to the system and the initial enzyme concentrations. Simulations of long-term evolution confirmed all analytical and numerical predictions, even though we relaxed the simplifying assumptions used in the analytical treatment.
Functional and ultrastructural analysis of reafferent mechanosensation in larval zebrafish
Authors: Odstrcil Iris , Petkova Mariela D. , Haesemeyer Martin , Boulanger-Weill Jonathan , Nikitchenko Maxim , Gagnon James A. , Oteiza Pablo , Schalek Richard , Peleg Adi , Portugues Ruben , Lichtman Jeff , Engert Florian 
Published: May 2021

AbstractAll animals need to differentiate between exafferent stimuli, which are caused by the environment, and reafferent stimuli, which are caused by their own movement. In the case of mechanosensation in aquatic animals, the exafferent inputs are water vibrations in the animal’s proximity, which need to be distinguished from the reafferent inputs arising from fluid drag due to locomotion. Both of these inputs are detected by the lateral line, a collection of mechanosensory organs distributed along the surface of the body.In this study, we characterize in detail how the hair cells, which are the receptor cells of the lateral line, discriminate between such reafferent and exafferent signals in zebrafish larvae. Using dye labeling of the lateral line nerve, we visualize two parallel descending inputs that can influence lateral line sensitivity. We combine functional imaging with ultra-structural EM circuit reconstruction to show that cholinergic signals originating from the hindbrain transmit efference copies that cancel out self-generated reafferent stimulation during locomotion, and that dopaminergic signals from the hypothalamus may have a role in threshold modulation both in response to locomotion and salient stimuli. We further gain direct mechanistic insight into the core components of this circuit by loss-of-function perturbations using targeted ablations and gene knockouts.We propose that this simple circuit is the core implementation of mechanosensory reafferent suppression in these young animals and that it might form the first instantiation of state-dependent modulation found at later stages in development.
Heme oxygenase limits mycobacterial infection-induced ferroptosis
Authors: Luo Kaiming , Stocker Roland , Britton Warwick J , Kikuchi Kazu , Oehlers Stefan H 
Published: May 2021

AbstractIron homeostasis is essential for both sides of the host-pathogen interface. Restricting access of iron slows bacterial growth while iron is also a necessary co-factor for host immunity. Heme oxygenase 1 (HMOX1) is a critical regulator of iron homeostasis that catalyses the liberation of iron during degradation of heme. It is also a stress-responsive protein that can be rapidly upregulated and confers protection to the host. Although a protective role of HMOX1 has been demonstrated in a variety of diseases, the role of HMOX1 inMycobacterium tuberculosisinfection is equivocal across experiments with different host-pathogen combinations. Here we use the natural host-pathogen pairing of the zebrafish-Mycobacterium marinuminfection platform to study the role of zebrafish heme oxygenase in mycobacterial infection. We identify zebrafish Hmox1a as the relevant functional paralog of mammalian HMOX1 and demonstrate a conserved role for Hmox1a in protecting the host from mycobacterial infection. Using genetic and chemical tools, we show zebrafish Hmox1a protects the host against mycobacterial infection by reducing infection-induced iron accumulation and ferroptosis.
The genomic landscape of early stage ovarian high grade serous carcinoma
Authors: Cheng Z. , Mirza H. , Ennis D.P. , Smith P. , Gavarró L. Morrill , Sokota C. , Giannone G. , Goranova T. , Bradley T. , Piskorz A. , Lockley M. ,   the BriTROC-1 Investigators^, Kaur B. , Singh N. , Tookman L.A. , Krell J. , McDermott J. , Macintyre G. , Markowetz F. , Brenton J.D. , McNeish I.A. 
Published: May 2021

AbstractPurposeHigh grade serous carcinoma (HGSC) is the commonest type of ovarian cancer. Nearly all HGSC cases are diagnosed at late stage and it is not clear whether early stage HGSC has unique characteristics compared to late stage tumours.Experimental DesignWe analysed samples from 45 patients with FIGO stage I - IIA HGSC - 40 from the pathology archives of three large UK cancer centres and 5 from the BriTROC-1 study. We performed shallow whole genome sequencing (sWGS) and targeted next generation sequencing to investigate somatic mutations and copy number alterations. We compared results to 51 stage IIIC/IV HGSC patients from the BriTROC-1 study.ResultsThere was no difference in median age between the early stage (median 61.3 years, range 40-84) and late stage (median 62.3 years, range 34-76) patients at diagnosis.TP53mutations were near-universal (92% early stage, 100% late stage samples) and there were no significant differences in the rates of other somatic mutations, includingBRCA1andBRCA2, or focal copy number alterations between early- and late-stage cohorts. There were also no unique amplifications or deletions in either cohort. However, median ploidy was greater in late stage (median 3.1) than early stage (median 2.0) samples. In addition, there were higher numbers of breakpoints per 10MB and per chromosome arm and higher absolute copy number in late stage than early stage cohorts; early stage samples had longer segment length. Overall copy number signature exposures were significantly different between early and late stage samples with greater signature 3 exposure in early stage and greater signature 4 in late stage. Both simplex plot and unsupervised hierarchical clustering suggested that a subset of late stage samples retain early stage appearances with high signature 3 and co-clustering with the early stage samplesConclusionsThese data suggest that there are no unique mutations or focal copy number alterations in early stage HGSC. However, whole genome duplication is significantly more common in late-stage disease, suggesting evolution during disease progression. However, a subset of late stage HGSC retains early-stage features, which are associated with improved overall survival.
Cross-fitted instrument: a blueprint for one-sample Mendelian Randomization
Authors: Denault William R.P. , Bohlin Jon , Page Christian M. , Burgess Stephen , Jugessur Astanand 
Published: May 2021

SummaryBias from weak instruments may undermine the ability to estimate causal effects in instrumental variable regression (IVR). We present here a simple solution for handling weak instrument bias by introducing a new type of instrumental variable called ‘cross-fitted instrument’ (CFI). CFI splits the data at random and estimates the impact of the instrument on the exposure in each partition. The estimates are then used to perform an IVR on each partition. We adapt CFI to Mendelian randomization (MR) and term this adaptation ‘Cross-Fitting for Mendelian Randomization’ (CFMR). A major advantage of CFMR is its use of all the available data to select genetic instruments, as opposed to traditional two-sample MR where a large part of the data is only used for instrument selection. Consequently, CFMR has the potential to enhance the power of MR in a meta-analysis setting by enabling an unbiased one-sample MR to be performed in each cohort prior to meta-analyzing the results across all the cohorts. In a similar fashion, CFMR enables a cross-ethnic MR analysis by accounting for ethnic heterogeneity, which is particularly important in consortia-led meta-analyses where the participating cohorts might be of different ethnicities. To our knowledge, there are currently no MR approach that can account for such heterogeneity. Finally, CFMR enables the application of MR to exposures that are rare or difficult to measure, which would normally preclude their analysis in the regular two-sample MR setting.Key messagesWe develop a new method to enable an unbiased one-sample Mendelian Randomization.The new method provides the same power as the standard two-sample Mendelian Randomization approach and does not require summary statistics from a genome-wide association study in an independent cohort.Our approach enables a cross-ethnic instrumental variable regression to account for heterogeneity in a sample consisting of multiple ethnicities.
A 3D molecular map of the cavefish neural plate illuminates eyefield organization and its borders in vertebrates
Authors: Agnès François , Torres-Paz Jorge , Michel Pauline , Rétaux Sylvie 
Published: May 2021

AbstractThe vertebrate retinas originate from a specific anlage in the anterior neural plate called the eyefield. The eyefield shares its anterior border with the prospective telencephalon and is in contact ventrally and posteriorly with hypothalamic and diencephalic precursors. Eyefield identity is conferred by a set of “eye transcription factors”, whose combinatorial expression has not been precisely characterized. Here, we use the dimorphic teleost speciesAstyanax mexicanus, which develops proper eyes in the wild type and smaller colobomatous eyes in the blind cavefish embryo, to unravel the molecular anatomy of the eyefield and its micro-evolutionary variations in the twoAstyanaxmorphs. Using a series of markers (Rx3, Pax6, CxCr4b, Zic1, Lhx2, Emx3, Nkx2.1), we draw a comparative 3D expression map at the end of gastrulation/onset of neurulation, which highlights hyper-regionalization of the eyefield into sub-territories of distinct sizes, shapes, cell identities and putative fates along the three body axes. We also discover sub-domains within the prospective telencephalon, and we characterize cell identities at the frontiers of the eyefield. Analyses at the tissue scale and single cell level show variations in volumes and shapes of eyefield subdivisions as well as cellular gene expression levels and identity changes in cavefish. The ventro-medial border and the anterior border of the eyefield contain cells co-expressing hypothalamic and telencephalic marker, respectively, in cavefish embryos. Altogether, we provide a new model of eyefield patterning in 3D and suggest a developmental origin for the emergence of the coloboma phenotype in the natural mutant cavefish embryo.
Members of theLegionella pneumophilaSde Family Target Tyrosine Residues for Phosphoribosyl-Linked Ubiquitination
Authors: Zhang Mengyun , McEwen Joseph M. , Sjoblom Nicole M. , Kotewicz Kristin M. , Isberg Ralph R. , Scheck Rebecca A. 
Published: May 2021

AbstractLegionella pneumophilaestablishes a replication vacuole by translocating hundreds of protein effectors through a type IV secretion system (T4SS). Among these translocated effectors are members of the Sde family, which catalyze phosphoribosyl-linked ubiquitination (pR-Ub) of host targets. Previous work has posited that Sde proteins solely target serine (Ser) residues within acceptor protein substrates. We show here that SdeC-mediated pR-Ub modification results from a stepwise reaction that also modifies tyrosine (Tyr) residues. Unexpectedly, the presence of an HA tag on Ub resulted in poly-pR-ubiquitination, consistent with the HA tag acting as an acceptor target. Interrogation of phosphoribosyl-linked HA-Ub revealed that Tyr4 was the preferred targeted residue, based on LC-MS/MS analysis of the crosslinked product. Further analysis using synthetic HA variants revealed promiscuous modification of Tyr, as crosslinking was prevented only by constructing a triple mutant in which all three Tyr within the HA sequence were substituted with Phe. Although previous work has indicated that Ser is the sole acceptor residue, we found no evidence of Ser preference over Tyr using Tyr->Ser replacement mutants. This work demonstrates that pR-ubiquitination by the Sde family is not limited to Ser-modification as previously proposed, and broadens the potential sites targeted by this family.
Precision environmental health monitoring by longitudinal exposome and multi-omics profiling
Authors: Gao Peng , Shen Xiaotao , Zhang Xinyue , Jiang Chao , Zhang Sai , Zhou Xin , Schüssler-Fiorenza Rose Sophia Miryam , Snyder Michael 
Published: May 2021

AbstractConventional environmental health studies primarily focused on limited environmental stressors at the population level, which lacks the power to dissect the complexity and heterogeneity of individualized environmental exposures. Here we integrated deep-profiled longitudinal personal exposome and internal multi-omics to systematically investigate how the exposome shapes an individual’s phenome. We annotated thousands of chemical and biological components in the personal exposome cloud and found they were significantly correlated with thousands of internal biomolecules, which was further cross validated using corresponding clinical data. In particular, our results showed that agrochemicals (e.g., carcinogenic pesticides, fungicides, and herbicides) and fungi predominated in the highly diverse and dynamic personal exposome, and the biomolecules and pathways related to the individual’s immune system, kidneys, and liver were highly correlated with the personal external exposome. Overall, our findings demonstrate dynamic interactions between the personal exposome and internal multi-omics and provide important insights into the impact of the environmental exposome on precision health.