bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel low-avidity glypican-3 specific CARTs resist exhaustion and mediate durable antitumor effects against hepatocellular carcinoma
Authors: Caraballo Galva Leidy D , Jiang Xiaotao , Hussein Mohamed S , Zhang Huajun , Mao Rui , Brody Pierce , Chi Xiangyang , Peng Yibing , He Aiwu Ruth , Kehinde-Ige Mercy , Sadek Ramses , Qiu Xiangguo , Shi Huidong , He Yukai 
Published: July 2021

AbstractChimeric antigen receptor engineered T cells (CARTs) are being developed to treat solid tumors including hepatocellular carcinoma (HCC). However, thus far, CARTs have not been as effective against solid tumors as compared to blood cancers. A main reason is that, once infiltrating into a solid tumor mass, CARTs are surrounded and chronically stimulated by persistent target antigens, which may drive them to exhaustion. We hypothesize that, due to weak engagement, low-avidity CARTs will resist the antigen-driven exhaustion and apoptosis and maintain effector functions in solid tumors, generating durable antitumor effects. To test this idea, we developed a novel human glypican-3 (hGPC3) specific antibody (8F8) that binds an epitope close to that of GC33 (the frequently used high-affinity antibody), but with ~17 folds lower affinity. In vitro, the low-avidity 8F8 CART killed tumor cells and produced effector cytokines to the same extent as high-avidity GC33 CART. Remarkably, however, 8F8 CART expanded and persisted to a greater extent than GC33 CART in vivo, resulting in durable responses against HCC xenografts. Compared to GC33 CARTs, there were significantly more (5 times) 8F8-BBz CART detected in the tumor mass. Importantly, the tumor infiltrating 8F8 CARTs were less apoptotic and more resistant to exhaustion, revealed by their enhanced and durable effector functions overtime. We predict that this novel low-avidity 8F8-BBz CART has a greater potential than mainstream high-avidity CARTs in effectively treating patients with HCC or other hGPC3+ solid tumors.
Homology Modelling, In Silico Prediction And Characterization Of Cytochrome c oxidase In Cyprinus carpio And Tubifex tubifex And Molecular Docking Studies Between The Modelled Protein And Three Commonly Used Surfactants Sodium Dodecyl Sulphate, Cetylpyridinium Chloride And Sodium Laureth Sulphate
Authors: Bhattacharya Ritwick , Daoud Ismail , Chatterjee Arnab , Chatterjee Soumendranath , Saha Nimai Chandra 
Published: July 2021

AbstractThe purpose of this work is to evaluate the homology modeling, in silico prediction, and characterisation of Cytochrome c oxidase from Cyprinus carpio and Tubifex tubifex, as well as molecular docking experiments between the modelled protein and three frequently used surfactants. Using the template crystal structure of bovine heart Cytochrome c oxidase, homology modeling of Cytochrome c oxidase (Subunit 2) of Cyprinus carpio (Accession # P24985) and Cytochrome c oxidase (Subunit 1) of Tubifex tubifex (Accession # Q7YAA6) was conducted. The model structure was improved further with 3Drefine, and the final 3D structure was verified with PROCHEK and ERRATA. The physiochemical, as well as the stereochemical parameters of the modelled protein, were evaluated using various tools like ExPASy’s ProtParam, Hydropathy Analysis and EMBOSS pepwheel. The projected model was then docked with toxic ligands, Sodium dodecyl sulfate (SDS), Cetylpyridinium chloride (CPC), and Sodium laureth sulfate (SLES), whose 3D structures were obtained from the Uniprot database. CPC interacted best with Cytochrome c oxidase subunit 2 of Cyprinus carpio and Cytochrome c oxidase subunit 1 of Tubifex tubifex, according to our findings. Furthermore, in the case of all surfactants, hydrophobic interactions with the active site amino acid residues of the modelled protein were observed to be more common than hydrogen bonds and salt bridges. Molecular simulation studies exhibited that the surfactants alter the structural flexibility of the predicted proteins. Hence it may be inferred that the surfactants might alter the structure and dynamics of Cytochrome c oxidase of both worm and fish.
Thalamic bursting and the role of timing and synchrony in thalamocortical signaling in the awake mouse
Authors: Borden Peter Y , Wright Nathaniel C , Morrissette Arthur E , Jaeger Dieter , Haider Bilal , Stanley Garrett B 
Published: July 2021

SummaryThe thalamus controls transmission of sensory signals from periphery to cortex, ultimately shaping perception. Despite this significant role, dynamic thalamic gating and the consequences for downstream cortical sensory representations have not been well studied in the awake brain. We optogenetically modulated the ventro-posterior medial thalamus in the vibrissa pathway of the awake mouse, and measured spiking activity in the thalamus, and activity in primary somatosensory cortex (S1) using extracellular electrophysiology and genetically encoded voltage imaging. Thalamic hyperpolarization significantly enhanced thalamic sensory-evoked bursting, yet surprisingly the S1 cortical response was not amplified, but instead timing precision was significantly increased, spatial activation more focused, and there was an increased synchronization of cortical inhibitory neurons. A thalamocortical network model implicates the modulation of precise timing of feedforward thalamic population spiking, presenting a highly sensitive, timing-based gating of sensory signaling to cortex.
Motor dysfunction in Drosophila melanogaster as a biomarker for developmental neurotoxicity
Authors: Cabrita Ana , Medeiros Alexandra M. , Pereira Telmo , Rodrigues António Sebastião , Kranendonk Michel , Mendes César S. 
Published: July 2021

AbstractHumans interact with numerous chemical compounds with direct health implications, with several able to induce developmental neurotoxicity (DNT), which bear developmental, behavioral, and cognitive consequences from a young age. Current guidelines for DNT testing are notably costly, time consuming, and unsuitable for testing large numbers of chemicals. Therefore, there is a need for adequate alternatives to conventional animal testing for neurotoxicity and DNT. Here we show that detailed kinematic analysis can provide a strong indicator for DNT, using known (chlorpyrifos, CPS) or putative (β-N-methylamino-L-alanine, BMAA) neurotoxic compounds. We exposed Drosophila melanogaster to these compounds during development and evaluated for common general toxicity — notably developmental survival and pupal positioning, together with the FlyWalker system, a detailed adult kinematics evaluation method.At concentrations that do not induce general toxicity, the solvent DMSO had a significant effect on kinematic parameters. Nonetheless, CPS not only induced developmental lethality but also significantly impaired coordination in comparison to DMSO, altering 16 motor parameters, validating the usefulness of our kinematic approach.Interestingly, BMAA, although not lethal during development, induced a dose-dependent motor decay, targeting most parameters in young adult animals, phenotypically resembling normally aged, non-exposed flies. This effect was subsequently attenuated during ageing, indicating an adaptive response. Furthermore, BMAA induced an abnormal terminal differentiation of leg motor neurons, without inducing degeneration, underpinning the observed altered mobility phenotype. Overall, our results support our kinematic approach as a novel, highly sensitive and reliable tool to assess potential DNT of chemical compounds.
Atp13a5 Marker Reveals Pericytes of The Central Nervous System in Mice
Authors: Guo Xinying , Ge Tenghuan , Xia Shangzhou , Wu Haijian , Colt Mark , Xie Xiaochun , Zhang Bangyan , Zeng Jianxiong , Chen Jian-Fu , Zhu Donghui , Montagne Axel , Gao Fan , Zhao Zhen 
Published: July 2021

SummaryPerivascular mural cells including vascular smooth cells (VSMCs) and pericytes are integral components of the vascular system. In the central nervous system (CNS), pericytes are also known as the guardian of the blood-brain barrier, blood-spinal cord barrier and blood-retinal barrier, and play key roles in maintaining cerebrovascular and neuronal functions. However, the functional difference between CNS and peripheral pericytes has not been resolved at the genetic and molecular levels. Hence, the generation of reliable CNS pericyte-specific models and genetic tools remains very challenging. Here, we report a new CNS pericyte marker in mice. This cation-transporting ATPase 13A5 (Atp13a5) marker is highly specific to the pericytes in brain, spinal cord and retina. We generated a transgenic model with a knock-in tdTomato reporter and Cre recombinase. The tdTomato reporter reliably labels the CNS pericytes, but not found in any other CNS cell types including closely related VSMCs, or in peripheral organs. More importantly, Atp13a5 is turned on at embryonic day E15, suggesting brain pericytes are shaped by the developing neural environment. We hope that the new tools will allow us to further explore the heterogeneity of pericytes and achieve a better understanding of CNS pericytes in health and diseases.
A novel imaging ligand as a biomarker for mutant huntingtin-lowering in Huntington’s disease
Authors: Bertoglio Daniele , Bard Jonathan , Hessmann Manuela , Liu Longbin , Gärtner Annette , Lombaerde Stef De , Huscher Britta , Zajicek Franziska , Miranda Alan , Peters Finn , Herrmann Frank , Schaertl Sabine , Vasilkovska Tamara , Brown Christopher J , Johnson Peter D , Prime Michael E , Mills Matthew R , Van der Linden Annemie , Mrzljak Ladislav , Khetarpal Vinod , Wang Yuchuan , Marchionini Deanna M , Skinbjerg Mette , Verhaeghe Jeroen , Dominguez Celia , Staelens Steven , Munoz-Sanjuan Ignacio 
Published: July 2021

AbstractHuntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in thehuntingtin(HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (PolyQ) tract. While several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, no method is currently available to visualize mHTT levels in the living brain. Here we demonstrate the development of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with11C ([11C]CHDI-180R) enables non-invasive monitoring of mHTT pathology in the brain and can track region-and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression. We further show that therapeutic agents that lower mHTT in the striatum have a functional restorative effect that can be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.
Contribution of opsins and chromophores to cone pigment variation across populations of Lake Victoria cichlids
Authors: Wilwert Elodie , Etienne Rampal S. , van de Zande Louis , Maan Martine E. 
Published: July 2021

AbstractAdaptation to heterogeneous sensory environments has been implicated as a key parameter in speciation. Cichlid fish are a textbook example of divergent visual adaptation, mediated by variation in the sequences and expression levels of cone opsin genes (encoding the protein component of visual pigments). In some vertebrates including fish, visual sensitivity is also tuned by the ratio of Vitamin A1/A2-derived chromophores (i.e. the light-sensitive component of the visual pigment, bound to the opsin protein), where higher proportions of A2 cause a more red-shifted wavelength absorbance. Here, we explore variation in chromophore ratios across multiple cichlid populations in Lake Victoria, using as a proxy the enzyme CYP27C1 that catalyses the conversion of Vitamin A1-into A2. We focus on sympatric Pundamilia cichlids, where species with blue or red male coloration co-occur at multiple islands, but occupy different depths and consequently different visual habitats. In the red species, we found higher cyp27c1 expression in populations from turbid-water than from clear-water locations, but there was no such pattern in the blue species. Across populations, differences between the sympatric species in cyp27c1 expression had a consistent relationship with species differences in opsin expression patterns, but the red/blue identity reversed between clear- and turbid-water locations. To assess the contribution of heritable versus environmental causes of variation, we tested whether light manipulations induce a change in cyp27c1 expression in the laboratory. We found that cyp27c1 expression was not influenced by experimental light conditions, suggesting that the observed variation in the wild is due to genetic differences. Establishing the biological importance of this variation requires testing the link between cyp27c1 expression and A1/A2 ratios in the eye, as well as its consequences for visual performance.
Aqueous extract ofPhyllanthus niruriprotects against severe malaria by blocking erythrocyte invasion and modulating the host immune response
Authors: Olawale Jeje Temitope , Bando Hironori , Fukuda Yasuhiro , Oluwafemi Ibukun Emmanuel , Kato Kentaro 
Published: July 2021

ABSTRACTPlasmodium falciparumparasites are the major cause of malaria across Africa. Due to the appearance of multi-drug resistant parasites, new antimalarial drugs are needed. The medicinal plantPhyllanthus niruriis being used to treat fever and other symptoms of malaria in Nigeria; however, little is known about its antimalarial mechanisms. Here, we show that aqueous extract ofP. niruri(PE) has multiple antimalarial effects, including anti-parasitic and host immunomodulatory activity. We found that co-culture ofP. falciparumwith PE drastically reduced parasite number, but PE did not inhibit parasite development or rupture; rather, it blocked erythrocytes invasion. In addition, we identified Astragalin as one of the antimalarial compounds which are contained in PE. Moreover, we found that PE suppresses the inflammatory activity and apoptosis of immune cells (T cells) and astrocytes and neurons in the central nervous system (CNS). Furthermore, we confirmed that oral administration of PE to mice suppressed parasite growth, excessive inflammation, CNS dysfunction, and the development of experimental cerebral malaria in anin vivomurine malaria model. Our findings demonstrate that PE has multiple effects on malaria progression, targeting both parasite and host cells.
Environmental differences explain subtle yet detectable genetic structure in a widespread pollinator
Authors: Glück Marcel , Geue Julia C. , Thomassen Henri. A. 
Published: July 2021

AbstractBackgroundThe environment is a strong driver of genetic structure in many natural populations, yet often neglected in population genetic studies. This may be a particular problem in vagile species, where subtle structure cannot be explained by limitations to dispersal. These species might falsely be considered panmictic and hence potentially mismanaged. Here we analysed the genetic structure in an economically important and widespread pollinator, the buff-tailed bumble bee (Bombus terrestris), which is considered to be quasi-panmictic at mainland continental scales. We first quantified population structure in Romania and Bulgaria with spatially implicit Fst and Bayesian clustering analyses. We then incorporated environmental information to infer the influence of the permeability of the habitat matrix between populations (resistance distances) as well as environmental differences among sites in explaining population divergence.ResultsGenetic structure of the buff-tailed bumble bee was subtle and not detected by Bayesian clustering. As expected, geographic distance and habitat permeability were not informative in explaining the spatial pattern of genetic divergence. Yet, environmental variables related to temperature, vegetation and topography were highly informative, explaining between 33 and 39% of the genetic variation observed.ConclusionsWhere in the past spatially implicit approaches had repeatedly failed, incorporating environmental data proved to be highly beneficial in detecting and unravelling the drivers of genetic structure in this vagile and opportunistic species. Indeed, structure followed a pattern of isolation by environment, where the establishment of dispersers is limited by environmental differences among populations, resulting in the disruption of genetic connectivity and the divergence of populations through genetic drift and divergent natural selection. With this work, we highlight the potential of incorporating environmental differences among population locations to complement the more traditional approach of isolation by geographic distance, in order to obtain a holistic understanding of the processes driving structure in natural populations.
BioCantor: a Python library for genomic feature arithmetic in arbitrarily related coordinate systems
Authors: Russell Pamela H. , Fiddes Ian T. 
Published: July 2021

AbstractMotivationBioinformaticians frequently navigate among a diverse set of coordinate systems: for example, converting between genomic, transcript, and protein coordinates. The abstraction of coordinate systems and feature arithmetic allows genomic workflows to be expressed more elegantly and succinctly. However, no publicly available software library offers fully featured interoperable support for multiple coordinate systems. As such, bioinformatics programmers must either implement custom solutions, or make do with existing utilities, which may lack the full functionality they require.ResultsWe present BioCantor, a Python library that provides integrated library support for arbitrarily related coordinate systems and rich operations on genomic features, with I/O support for a variety of file formats.Availability and implementationBioCantor is implemented as a Python 3 library with a minimal set of external dependencies. The library is freely available under the MIT license at https://github.com/InscriptaLabs/BioCantor and on the Python Package Index at https://pypi.org/project/BioCantor/. BioCantor has extensive documentation and vignettes available on ReadTheDocs at https://biocantor.readthedocs.io/en/latest/.
Cross-linkers at growing microtubule ends generate forces that drive actin transport
Authors: Alkemade Celine , Wierenga Harmen , Volkov Vladimir A. , López Magdalena Preciado , Akhmanova Anna , ten Wolde Pieter Rein , Dogterom Marileen , Koenderink Gijsje H. 
Published: July 2021

AbstractThe actin and microtubule cytoskeletons form active networks in the cell that can contract and remodel, resulting in vital cellular processes as cell division and motility. Motor proteins play an important role in generating the forces required for these processes, but more recently the concept of passive cross-linkers being able to generate forces has emerged. So far, these passive cross-linkers have been studied in the context of separate actin and microtubule systems. Here, we show that crosslinkers also allow actin and microtubules to exert forces on each other. More specifically, we study single actin filaments that are cross-linked to growing microtubule ends, using in vitro reconstitution, computer simulations, and a minimal theoretical model. We show that microtubules can transport actin filaments over large (micrometer-range) distances, and find that this transport results from two antagonistic forces arising from the binding of cross-linkers to the overlap between the actin and microtubule filaments. The cross-linkers attempt to maximize the overlap between the actin and the tip of the growing microtubules, creating an affinity-driven forward condensation force, and simultaneously create a competing friction force along the microtubule lattice. We predict and verify experimentally how the average transport time depends on the actin filament length and the microtubule growth velocity, confirming the competition between a forward condensation force and a backward friction force. In addition, we theoretically predict and experimentally verify that the condensation force is of the order of 0.1 pN. Thus, our results reveal a new mechanism for local actin remodeling by growing microtubules.Significance StatementComplex cellular processes such as cell migration require coordinated remodeling of both the actin and the microtubule cytoskeleton. The two networks for instance exert forces on each other via active motor proteins. Here we show that, surprisingly, coupling via passive cross-linkers can also result in force generation. We specifically study the transport of actin filaments by growing microtubule ends. We show by cell-free reconstitution experiments, computer simulations, and theoretical modeling that this transport is driven by the affinity of the cross-linker for the chemically distinct microtubule tip region. Our work predicts that growing microtubules could potentially rapidly relocate newly nucleated actin filaments to the leading edge of the cell and thus boost migration.
Zygotic contractility awakening during mouse preimplantation development
Authors: Özgüç Özge , de Plater Ludmilla , Kapoor Varun , Tortorelli Anna Francesca , Maître Jean-Léon 
Published: July 2021

AbstractActomyosin contractility is a major engine of preimplantation morphogenesis, which starts at the 8-cell stage during mouse embryonic development. Contractility becomes first visible with the appearance of periodic cortical waves of contraction (PeCoWaCo), which travel around blastomeres in an oscillatory fashion. How contractility of the mouse embryo becomes active remains unknown. We have taken advantage of PeCoWaCo to study the awakening of contractility during preimplantation development. We find that PeCoWaCo become detectable in most embryos only after the 2ndcleavage and gradually increase their oscillation frequency with each successive cleavage. To test the influence of cell size reduction during cleavage divisions, we use cell fusion and fragmentation to manipulate cell size across a 20-60 μm range. We find that the stepwise reduction in cell size caused by cleavage divisions does not explain the presence of PeCoWaCo or their accelerating rhythm. Instead, we discover that blastomeres gradually decrease their surface tensions until the 8-cell stage and that artificially softening cells enhances PeCoWaCo prematurely. Therefore, during cleavage stages, cortical softening awakens zygotic contractility before preimplantation morphogenesis.
Single-cell bisulfite sequencing of spermatozoa from lean and obese humans reveals potential for the transmission of epimutations
Authors: Andersen Emil , Clark Stephen , Ingerslev Lars , Lundell Leonidas , Reik Wolf , Barrès Romain 
Published: July 2021

ABSTRACTEpigenetic marks in gametes modulate developmental programming after fertilization. Spermatozoa from obese men exhibit distinct epigenetic signatures compared to lean men, however, whether epigenetic differences are concentrated in a sub-population of spermatozoa or spread across the ejaculate population is unknown. Here, by using whole-genome single-cell bisulfite sequencing on 87 motile spermatozoa from 8 individuals (4 lean and 4 obese), we found that spermatozoa within single ejaculates are highly heterogeneous and contain subsets of spermatozoa with marked imprinting defects. Comparing lean and obese subjects, we discovered methylation differences across two large CpG dense regions located near PPM1D and LINC01237. These findings confirm that sperm DNA methylation is altered in human obesity and indicate that single ejaculates contain subpopulations of spermatozoa carrying distinct DNA methylation patterns. Distinct epigenetic patterns of spermatozoa within an ejaculate may result in different intergenerational effects and therefore influence strategies aiming to prevent epigenetic-related disorders in the offspring.