bluuebunny/crossref_metadata_2025 huggingface dataset:
Language models enable zero-shot prediction of the effects of mutations on protein function
Authors: Meier Joshua , Rao Roshan , Verkuil Robert , Liu Jason , Sercu Tom , Rives Alexander
Published: July 2021

Modeling the effect of sequence variation on function is a fundamental problem for understanding and designing proteins. Since evolution encodes information about function into patterns in protein sequences, unsupervised models of variant effects can be learned from sequence data. The approach to date has been to fit a model to a family of related sequences. The conventional setting is limited, since a new model must be trained for each prediction task. We show that using only zero-shot inference, without any supervision from experimental data or additional training, protein language models capture the functional effects of sequence variation, performing at state-of-the-art.
An energy-dissipative state of the major antenna complex of plants
Authors: Bru Pierrick , Steen Collin J. , Park Soomin , Amstutz Cynthia L. , Sylak-Glassman Emily J. , Lam Lam , Fekete Agnes , Mueller Martin J. , Longoni Fiamma , Fleming Graham R. , Niyogi Krishna K. , Malnoë Alizée
Published: July 2021

Plants and algae are faced with a conundrum: harvesting sufficient light to drive their metabolic needs while dissipating light in excess to prevent photodamage, a process known as non-photochemical quenching. A slowly relaxing form of energy dissipation, termed qH, is critical for plants’ survival under abiotic stress. Here, we tested whether we could isolate photosynthetic subcomplexes (from plants in which qH was induced) that would remain in an energy-dissipative state. Interestingly chlorophyll fluorescence lifetimes were decreased by qH in isolated major trimeric antenna complexes, providing a natively quenched complex with physiological relevance to natural conditions. Next, we monitored the changes in thylakoid pigment, protein or lipid content of antenna with active or inactive qH, and no evident differences were detected. Finally, we investigated whether specific antenna subunits of the major antenna were required for qH but found it insensitive to trimer composition. Because qH can occur in the absence of specific xanthophylls, and no changes in pigments were detected, we propose that the energy-dissipative state reported here may stem from chlorophyll-chlorophyll excitonic interaction.
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

Chimeric 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

The 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

The 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

Humans 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

Perivascular 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

Huntington’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

Adaptation 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

Plasmodium 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

Background

The 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.

Results

Genetic 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.

Conclusions

Where 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

Motivation

Bioinformaticians 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.

Results

We 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 implementation

BioCantor 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

The 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 Statement

Complex 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

Actomyosin 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

Epigenetic 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.
Novel method for clarifying faster interstitial flow in the intimal side of the aorta under intraluminal pressurization
Authors: Fukui Wataru , Yoshihiro Ujihara , Nakamura Masanori , Sugita Shukei
Published: July 2021

Hypertension causes aortic thickening, especially on the intimal side. Although the production of the extracellular matrix is observed, the type of mechanical stress that produces this response remains unclear. In this study, we hypothesize that the interstitial flow causes the thickening. To validate this claim, we proposed a novel method to measure the velocity distribution in the radial direction in the aorta, which has been unclear. A fluorescent dye was introduced in the lumen of the mouse thoracic aorta ex vivo, intraluminal pressure was applied, and a time-lapse image in the radial-circumferential plane was acquired under a two-photon microscope. The flow of the fluorescent dye from the intimal to the adventitial sides in the aorta was successfully observed. The acquired image was converted to a radial-time image (i.e., kymograph), and the flow velocity was quantified by applying the one-dimensional advection-diffusion equation to the fluorescent images. The results revealed a higher interstitial flow velocity in the aortic walls under higher intraluminal pressure and a higher velocity on the more intimal side. Thus, the interstitial flow is a candidate for the mechanical stress causing hyperplasia of the aorta under hypertension.
Tn5 transposase-based epigenomic profiling methods are prone to open chromatin bias
Authors: Wang Meng , Zhang Yi
Published: July 2021

Epigenetic studies of rare biological samples like mammalian oocytes and preimplantation embryos require low input or even single cell epigenomic profiling methods. To reduce sample loss and avoid inefficient immunoprecipitation, several chromatin immuno-cleavage-based methods using Tn5 transposase fused with Protein A/G have been developed to profile histone modifications and transcription factor bindings using small number of cells. The Tn5 transposase-based epigenomic profiling methods are featured with simple library construction steps in the same tube, by taking advantage of Tn5 transposase’s capability of simultaneous DNA fragmentation and adaptor ligation. However, the Tn5 transposase prefers to cut open chromatin regions. Our comparative analysis shows that Tn5 transposase-based profiling methods are prone to open chromatin bias. The high false positive signals due to biased cleavage in open chromatin could cause misinterpretation of signal distributions and dynamics. Rigorous validation is needed when employing and interpreting results from Tn5 transposase-based epigenomic profiling methods.
BioCCP.jl: Collecting Coupons in combinatorial biotechnology
Authors: Van Huffel Kirsten , Stock Michiel , De Baets Bernard
Published: July 2021

In combinatorial biotechnology, it is crucial for screening experiments to sufficiently cover the design space. In the BioCCP.jl package, we provide functions for minimum sample size determination based on the mathematical framework coined the Coupon Collector Problem. BioCCP.jl, including source code, documentation and a Pluto notebook is available at https://github.com/kirstvh/BioCCP.
Divergent assembly trajectories: a comparison of the plant and soil microbiome with plant communities in a glacier forefield
Authors: Junker Robert R. , He Xie , Otto Jan-Christoph , Ruiz-Hernández Victoria , Hanusch Maximilian
Published: July 2021

Community assembly is a result of dispersal, abiotic and biotic characteristics of the habitat as well as stochasticity. A direct comparison between the assembly of microbial and ‘macrobial’ organisms is hampered by the sampling of these communities in different studies, at different sites, or on different scales. In a glacier forefield in the Austrian Alps, we recorded the soil and plant microbiome (bacteria and fungi) and plants that occurred in the same landscape and in close proximity in the same plots. We tested five predictions deduced from assembly processes and revealed deviating patterns of assembly in these community types. In short, microbes appeared to be less dispersal limited than plants, soil microbes and plants strongly responded to abiotic factors whereas the leaf microbiome was plant species-specific and well buffered from environmental conditions. The observed differences in community assembly processes may be attributed to the organisms’ dispersal abilities, the exposure of the habitats to airborne propagules, and habitat characteristics. The finding that assembly is conditional to the characteristics of the organisms, the habitat, and the spatial scale under consideration is thus central for our understanding about the establishment and the maintenance of biodiversity.
Evolutionary origins of sexual dimorphism : Lessons from female-limited mimicry in butterflies.
Authors: Maisonneuve Ludovic , Smadi Charline , LLAURENS Violaine
Published: July 2021

The striking female-limited mimicry observed in some butterfly species is a text-book example of sexually-dimorphic trait submitted to intense natural selection. Two main evolutionary hypotheses, based on natural and sexual selection respectively, have been proposed. Predation pressure favouring mimicry toward defended species could be higher in females because of their slower flight, and thus overcome developmental constraints favouring the ancestral trait that limits the evolution of mimicry in males but not in females. Alternatively, the evolution of mimicry in males could be limited by females preference for non-mimetic males. However, the evolutionary origin of female preference for non-mimetic males remains unclear. Here, we hypothesise that costly sexual interactions between individuals from distinct sympatric species might intensify because of mimicry, therefore promoting female preference for non-mimetic trait. Using a mathematical model, we compare the evolution of female-limited mimicry when assuming either alternative selective hypotheses. We show that the patterns of divergence of male and female trait from the ancestral traits can differ between these selection regimes. We specifically highlight that divergence in females trait is not a signature of the effect of natural selection. Our results also evidence why female-limited mimicry is more frequently observed in Batesian mimics.
Quantitative characterisation of low abundant yeast mitochondrial proteins reveals compensation for haplo-insufficiency in different environments
Authors: Manousaki Alkisti , Bagnall James , Spiller David , Balarezo-Cisneros Laura Natalia , White Michael , Delneri Daniela
Published: July 2021

Quantification of low abundant membrane-binding proteins such as transcriptional factors and chaperones has been proved difficult even with the most sophisticated analytical technologies. Here we exploit and optimise the non-invasive Fluorescence Correlation Spectroscopy (FCS) for quantitation of low abundance proteins and as proof of principle we choose two interacting proteins involved in fission of mitochondria in yeast, Fis1p and Mdv1p. In Saccharomyces cerevisiae the recruitment of Fis1p and Mdv1p to mitochondria is essential for the scission of the organelles and the retention of functional mitochondrial structures in the cell. We used FCS in single, GFP-labelled live yeast cells to quantify the protein abundance in homozygote and heterozygote cells, and to investigate the impact of the environments on protein copy number, bound/unbound protein state and mobility kinetics. Both proteins were observed to localise predominantly at mitochondrial structures with the Mdv1p bound state increasing significantly in a strictly respiratory environment. Moreover, a compensatory mechanism which controls Fis1p abundance upon deletion of one allele was observed in Fis1p but not in Mdv1p, suggesting differential regulation of Fis1p and Mdv1p protein expression.
Intrinsic Functional Connectivity in the Default Mode Network Predicts Mnemonic Discrimination: A Connectome-based Modeling Approach
Authors: Wahlheim Christopher N. , Christensen Alexander P. , Reagh Zachariah M. , Cassidy Brittany S.
Published: July 2021

The ability to distinguish existing memories from similar perceptual experiences is a core feature of episodic memory. This ability is often examined using the Mnemonic Similarity Task in which people discriminate memories of studied objects from perceptually similar lures. Studies of the neural basis of such mnemonic discrimination have mostly focused on hippocampal function and connectivity. However, default mode network (DMN) connectivity may also support such discrimination, given that the DMN includes the hippocampus, and its connectivity supports many aspects of episodic memory. Here, we used connectome-based predictive modeling to identify associations between intrinsic DMN connectivity and mnemonic discrimination. We leveraged a wide range of abilities across healthy younger and older adults to facilitate this predictive approach. Resting-state functional connectivity in the DMN predicted mnemonic discrimination outside the MRI scanner, especially among prefrontal and temporal regions and including several hippocampal regions. This predictive relationship was stronger for younger than older adults, primarily for temporalprefrontal connectivity. The novel associations established here are consistent with mounting evidence that broader cortical networks including the hippocampus support mnemonic discrimination. They also suggest that age-related network disruptions undermine the extent that the DMN supports this ability. This study provides the first indication of how intrinsic functional properties of the DMN support mnemonic discrimination.
BERTax: taxonomic classification of DNA sequences with Deep Neural Networks
Authors: Mock Florian , Kretschmer Fleming , Kriese Anton , Böcker Sebastian , Marz Manja
Published: July 2021

Taxonomic classification, i.e., the identification and assignment to groups of biological organisms with the same origin and characteristics, is a common task in genetics. Nowadays, taxonomic classification is mainly based on genome similarity search to large genome databases. In this process, the classification quality depends heavily on the database since representative relatives have to be known already. Many genomic sequences cannot be classified at all or only with a high misclassification rate.

Here we presentBERTax, a program that uses a deep neural network to pre-cisely classify the superkingdom, phylum, and genus of DNA sequences taxonomically without the need for a known representative relative from a database. For this,BERTaxuses the natural language processing model BERT trained to represent DNA. We showBERTaxto be at least on par with the state-of-the-art approaches when taxonomically similar species are part of the training data. In case of an entirely novel organism, however,BERTaxclearly outperforms any existing approach. Finally, we show thatBERTaxcan also be combined with database approaches to further increase the prediction quality.

SinceBERTaxis not based on homologous entries in databases, it allows precise taxonomic classification of a broader range of genomic sequences. This leads to a higher number of correctly classified sequences and thus increases the overall information gain.
Neural excitation/inhibition imbalance and the treatment of severe depression
Authors: ten Doesschate Freek , Bruin Willem , Zeidman Peter , Abbott Christopher C. , Argyelan Miklos , Dols Annemieke , Emsell Louise , van Eijndhoven Philip F.P. , van Exel Eric , Mulders Peter C.R. , Narr Katherine , Tendolkar Indira , Rhebergen Didi , Sienaert Pascal , Vandenbulcke Mathieu , Verdijk Joey , van Verseveld Mike , Bartsch Hauke , Oltedal Leif , van Waarde Jeroen A. , van Wingen Guido A.
Published: July 2021

An influential hypothesis holds that depression is related to a neural excitation/inhibition imbalance, but its role in the treatment of depression remains unclear. Here, we show that unmedicated patients with severe depression demonstrated reduced inhibition of brain-wide resting-state networks relative to healthy controls. Patients using antidepressants showed inhibition that was higher than unmedicated patients and comparable to controls, but they still suffered from severe depression. Subsequent treatment with electroconvulsive therapy (ECT) reduced depressive symptoms, but its effectiveness did not depend on changes in network inhibition. Concomitant pharmacotherapy increased the effectiveness of ECT, but only when the strength of neural inhibition before ECT was within the normal range and not when inhibition was excessive. These findings suggest that reversing the excitation/inhibition imbalance may not be sufficient nor necessary for the effective treatment of severe depression, and that brain-state informed pharmacotherapy management may enhance the effectiveness of ECT.
Development and Validation Molecular Docking Analysis of Human serum albumin (HSA)
Authors: Ferrari Ivan Vito , Patrizio Paolo
Published: July 2021

Background

HAS (Human Serum Albumin) is a highly water-soluble globular plasma protein, with a relative molecular weight (g/mol) of 67 KDa, consisting of 585 amino acid residues. In this study, we have investigated the interaction of the Crystal structures complexed in human serum albumin at resolutions of 2.8 to 2.0: Camptothecin, 9-amino-camptothecin, Etoposide, Teniposide, Bicalutamide and Idarubicin, using a bioinformatic approach, estimated by Pyrx Virtual Screen Tool and AMDock (AMDock, Assisted Molecular Docking). We have analyzed a validated protocol, studying several parameters, as Binding Affinity, RMSD value, Ligand Efficiency, and Inhibition constant (Ki value).

Methods

Human Serum Albumin protein preparation was characterized with several programs, as Chimera, MGLTools 1.5.6, Swiss PDB Viewer Software to perform docking analysis by Autodock Vina estimated with Pyrx Software.

Results

In this work, we have found crystalized camptothecin, crystalized 9-amino-camptothecin and crystalized teniposide, gave excellent results for Binding Affinity, (kcal/mol), RMSD value (A°), inhibition constant Ki value (nM): -Binding Affinity of 9-amino-camptothecin (ca.−10 kcal/mol), camptothecin (−9 kcal/mol) and teniposide (−11 kcal/mol, -RMSD Value of 9 -amino-camptothecin (ca.1.8 Å), camptothecin (ca.2.2 Å) and teniposide (ca. 3.6 Å), - Ki Value: 9 -amino-camptothecin (ca 59 nM), camptothecin (ca 183 nM) and teniposide (ca 9 nM), -Ligand efficiency: of 9 -amino-camptothecin(ca −0.35 kcal/mol), camptothecin (ca −0.34 kcal/mol) and teniposide (ca −0.24 kcal/mol

Conclusions

We explored the best three crystallized ligand in Human Serum Albumin. Moreover, we observe a complete overlap, during the re-docking analysis phase, estimated by chimera Software. Therefore we have concluded that ID PDB Crystal 4L8U human serum albumin-Crystallised 9 -amino Camptothecin; ID PDB Crystal 4L9K human serum albumin-Crystallised Camptothecin and ID PDB Crystal 4L9Q human serum albumin-crystallized teniposide be used as a possible as a reference template protein to be compared with the target protein, by Docking molecular analysis.
Rapid divergence in vegetative morphology of a wind-pollinated plant between populations at contrasting densities
Authors: Tonnabel Jeanne , David Patrice , Pannell John
Published: July 2021

Plant sexual dimorphism is thought to evolve in response to sex-specific selection associated with competition for access to mates or resources, both of which will often be density-dependent. In wind-pollinated plants in particular, vegetative traits can have an important influence on both resource acquisition and the pollen dispersal and receipt, with potential conflict between these two components of fitness. We evaluated the role of plant density in shaping plant traits by measuring evolutionary responses in experimental populations of the sexually dimorphic wind-pollinated plant Mercurialis annua. After three generations of evolution, we observed divergence between high- and low-density populations in several vegetative traits, whereas there was no divergence for reproductive traits. A reversal in the direction of sexually dimorphic traits expressed in young plants evolved in both low- and high-density populations compared to the original population (stored as seeds). Compared to the source population, males at high density evolved to be taller when young, whereas at low density young females tended to become smaller. These results demonstrate that a simple change in plant density can induce rapid, age-dependent and sex-specific evolution in the ontogeny of vegetative organs, and illustrates the power of experimental evolution for investigating plant trait evolution.
One-week escitalopram intake shifts excitation-inhibition balance in the healthy female brain
Authors: Zsido Rachel G. , Molloy Eóin N. , Cesnaite Elena , Zheleva Gergana , Beinhölzl Nathalie , Scharrer Ulrike , Piecha Fabian A. , Regenthal Ralf , Villringer Arno , Nikulin Vadim V. , Sacher Julia
Published: July 2021

Neural health relies on cortical excitation-inhibition balance (EIB), with disrupted EIB underlying circuit dysfunction in several neuropsychiatric disorders. Previous research suggests links between increased cortical excitation and neuroplasticity induced by selective serotonin reuptake inhibitors (SSRIs). Whether there are modulations of EIB following SSRI-administration in the healthy human brain, however, remains unclear. To this end, we assessed changes in EIB following longitudinal escitalopram-intake. In a randomized, double-blind study protocol, a sample of 59 healthy female individuals on oral contraceptives underwent three resting-state electroencephalography recordings after daily administration of 20 mg escitalopram (n = 28) or placebo (n = 31) at baseline, after single dose, and after 1 week (steady state). We assessed 1/f slope of the power spectrum, a marker of EIB, compared individual trajectories of 1/f slope changes contrasting single dose and 1-week drug intake, and tested the relationship of escitalopram plasma levels and cortical excitatory and inhibitory balance shifts. Escitalopram-intake associated with decreased 1/f slope, indicating an EIB shift in favor of excitation. Furthermore, 1/f slope at baseline and after single dose of escitalopram predicted 1/f slope at steady state. Higher plasma escitalopram levels at single dose associated with better maintenance of these EIB changes throughout the drug administration week. Characterizing changes in 1/f slope during longitudinal SSRI-intake in healthy female individuals, we show that escitalopram shifted EIB in favor of excitation. These findings demonstrate the potential for 1/f slope to predict individual cortical responsivity to SSRIs and widen the neuroimaging lens by testing an interventional psychopharmacological design in a clearly-defined endocrinological state.
Community composition exceeds area as a predictor of long-term conservation value
Authors: O’Sullivan Jacob D. , Terry J. Christopher D. , Wilson Ramesh , Rossberg Axel G.
Published: July 2021

Conserving biodiversity often requires deciding which sites to prioritise for protection. Predicting the impact of habitat loss is a major challenge, however, since impacts can be distant from the perturbation in both space and time. Here we study the long-term impacts of habitat loss in a mechanistic metacommunity model in terms of both immediate extinctions and secondary species losses. We find that biomass-at-site, closely related to site area, is a poor predictor of long-term regional species losses following site removal. Knowledge of the compositional distinctness (average between-site Bray-Curtis dissimilarity) of the removed community can markedly improve the prediction of impacts at the regional scale, even when biotic responses play out at substantial spatial or temporal distance from the removed site. Fitting our model to empirical species-by-site tables describing Andean diatoms and Brazilian lichen-fungi, we show that compositional distinctness surpasses area as a predictor of long-term species losses in the empirically relevant parameter range. Our results robustly demonstrate that site area alone is not sufficient to gauge conservation priorities; analysis of compositional distinctness permits improved prioritisation at low cost.
HepT1-derived murine models of high-risk hepatoblastoma display vascular invasion, metastasis, and circulating tumor cells
Authors: Woodfield Sarah E. , Mistretta Brandon J. , Patel Roma H. , Ibarra Aryana M. , Fisher Kevin E. , Sarabia Stephen F. , Gandhi Ilavarasi , Reuther Jacquelyn , Starosolski Zbigniew , Badachhape Andrew , Shah Aayushi P. , Larson Samuel R. , Srivastava Rohit K. , Shi Yan , Whitlock Richard S. , Holloway Kimberly , Roy Angshumoy , Ghaghada Ketan B. , Lopez-Terrada Dolores , Gunaratne Preethi H. , Vasudevan Sanjeev A.
Published: July 2021

Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB.

Summary Statement

In this work, we developed and thoroughly characterized several unique models of hepatoblastoma derived from the HepT1 cell line that show high-risk features.