bluuebunny/crossref_metadata_2025 huggingface dataset:
Unification and extensive diversification of M/Orf3-related ion channel proteins in coronaviruses and other nidoviruses
Authors: Tan Yongjun , Schneider Theresa , Shukla Prakash K , Chandrasekharan Mahesh B , Aravind L , Zhang Dapeng
Published: February 2021

The coronavirus, Severe Acute Respiratory Syndrome (SARS)-CoV-2, responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic, has emphasized the need for a better understanding of the evolution of virus-host interactions. ORF3a in both SARS-CoV-1 and SARS-CoV-2 are ion channels (viroporins) implicated in virion assembly and membrane budding. Using sensitive profile-based homology detection methods, we unify the SARS-CoV ORF3a family with several families of viral proteins, including ORF5 from MERS-CoVs, proteins from beta-CoVs (ORF3c), alpha-CoVs (ORF3b), most importantly, the Matrix (M) proteins from CoVs, and more distant homologs from other nidoviruses. We present computational evidence that these viral families might utilize specific conserved polar residues to constitute an aqueous pore within the membrane-spanning region. We reconstruct an evolutionary history of these families and objectively establish the common origin of the M proteins of CoVs and Toroviruses. We also show that the divergent ORF3 clade (ORF3a/ORF3b/ORF3c/ORF5 families) represents a duplication stemming from the M protein in alpha- and beta-CoVs. By phyletic profiling of major structural components of primary nidoviruses, we present a hypothesis for their role in virion assembly of CoVs, ToroVs, and Arteriviruses. The unification of diverse M/ORF3 ion channel families in a wide range of nidoviruses, especially the typical M protein in CoVs, reveal a conserved, previously under-appreciated role of ion channels in virion assembly and membrane budding. We show that M and ORF3 are under different evolutionary pressures; in contrast to the slow evolution of M as core structural component, the ORF3 clade is under selection for diversification, which suggests it might act at the interface with host molecules and/or immune attack.
Institutional Change in the Banking Union: The Case of the Single Supervisory Mechanism
Authors: Schammo Pierre
Published: February 2021

This article is about institutional change in the Banking Union. It has two related aims. The first is to engage with the law of the Single Supervisory Mechanism (SSM)—the first pillar of the Banking Union—and in this context to discuss tensions that have lately emerged between the case law of the Court of Justice of the European Union (CJEU) and that of the German Federal Constitutional Court. The second, but main, aim of this article is to put the law of the SSM as it was enacted in the SSM Regulation, and as it was interpreted by the CJEU and by the German court, in a broader perspective of institutional change. For this purpose, this article adopts an interdisciplinary approach that seeks insights on institutional change in the political science literature. In particular, the article seeks to shed light on the role played by courts. In short, it argues that whilst the SSM is a story of change following an exogenous shock (ie the sovereign debt crisis), it is also an account of change and contestation between courts made possible by the ambiguities and incompleteness of the SSM rules. It will show that the evolution of the SSM is by no means frictionless and that it is only by tracing change from the point of the enactment of the law to its interpretation by the courts that one gains a real appreciation of the dynamics and salience of change within the SSM.
Criibacterium bergeronii gen. nov., sp. nov., a new member of the family Peptostreptococcaceae, isolated from human clinical samples
Authors: Maheux Andrée F. , Boudreau Dominique K. , Abed Jehane Y. , Bérubé Ève , Brodeur Stéphanie , Bernard Kathryn A. , Hashimi Ameena , Ducrey Éloïse , Guay Émilie F. , Raymond Frédéric , Corbeil Jacques , Domingo Marc-Christian , Roy Paul H. , Boissinot Maurice , Tocheva Elitza I. , Omar Rabeea F.
Published: February 2021

A rod-shaped, motile anaerobic bacterium, designated CCRI-22567T, was isolated from a vaginal sample of a woman diagnosed with bacterial vaginosis and subjected to a polyphasic taxonomic study. The novel strain was capable of growth at 30–42 °C (optimum, 42 °C), at pH 5.5–8.5 (optimum, pH 7.0–7.5) and in the presence of 0–1.5 % (w/v) NaCl (optimally at 0.5 % NaCl). The phylogenetic trees based on 16S rRNA gene sequences showed that strain CCRI-22567T forms a distinct evolutionary lineage independent of other taxa in the family

Peptostreptococcaceae

. Strain CCRI-22567T exhibited 90.1 % 16S rRNA gene sequence similarity to

Peptoanaerobacter stomatis

ACC19aT and 89.7 % to

Eubacterium yurii

subsp.

schtitka

ATCC 43716. The three closest organisms with an available whole genome were compared to strain CCRI-22567T for genomic relatedness assessment. The genomic average nucleotide identities (OrthoANIu) obtained with

Peptoanaerobacter stomatis

ACC19aT,

Eubacterium yurii

subsp.

margaretiae

ATCC 43715 and

Filifactor alocis

ATCC 35896T were 71.8, 70.3 and 69.6 %, respectively. Strain CCRI-22567T contained C18 : 1 ω9c and C18 : 1 ω9c DMA as the major fatty acids. The DNA G+C content of strain CCRI-22567T based on its genome sequence was 33.8 mol%. On the basis of the phylogenetic, chemotaxonomic and other phenotypic properties, strain CCRI-22567T is considered to represent a new genus and species within the family

Peptostreptococcaceae

, for which the name Criibacterium bergeronii gen. nov., sp. nov., is proposed. The type strain of Criibacterium bergeronii is CCRI-22567T (=LMG 31278T=DSM 107614T=CCUG 72594T).
rasterdiv - an Information Theory tailored R package for measuring ecosystem heterogeneity from space: to the origin and back
Authors: Rocchini Duccio , Thouverai Elisa , Marcantonio Matteo , Iannacito Martina , Da Re Daniele , Torresani Michele , Bacaro Giovanni , Bazzichetto Manuele , Bernardi Alessandra , Foody Giles M. , Furrer Reinhard , Kleijn David , Larsen Stefano , Lenoir Jonathan , Malavasi Marco , Marchetto Elisa , Messori Filippo , Montaghi Alessandro , Moudrý Vítězslav , Naimi Babak , Ricotta Carlo , Rossini Micol , Santi Francesco , Santos Maria J. , Schaepman Michael , Schneider Fabian , Schuh Leila , Silvestri Sonia , Šímová Petra , Skidmore Andrew K. , Tattoni Clara , Tordoni Enrico , Vicario Saverio , Zannini Piero , Wegmann Martin
Published: February 2021

Ecosystem heterogeneity has been widely recognized as a key ecological feature, influencing several ecological functions, since it is strictly related to several ecological functions like diversity patterns and change, metapopulation dynamics, population connectivity, or gene flow.

In this paper, we present a newRpackage -rasterdiv- to calculate heterogeneity indices based on remotely sensed data. We also provide an ecological application at the landscape scale and demonstrate its power in revealing potentially hidden heterogeneity patterns.

Therasterdivpackage allows calculating multiple indices, robustly rooted in Information Theory, and based on reproducible open source algorithms.
DROP: Molecular voucher database for identification ofDrosophilaparasitoids
Authors: Lue Chia-Hua , Buffington Matthew L. , Scheffer Sonja , Lewis Matthew , Elliott Tyler A. , Lindsey Amelia R. I. , Driskell Amy , Jandova Anna , Kimura Masahito T. , Carton Yves , Kula Robert R. , Schlenke Todd A. , Mateos Mariana , Govind Shubha , Varaldi Julien , Guerrieri Emilio , Giorgini Massimo , Wang Xingeng , Hoelmer Kim , Daane Kent M. , Abram Paul K. , Pardikes Nicholas A. , Brown Joel J. , Thierry Melanie , Poirié Marylène , Goldstein Paul , Miller Scott E. , Tracey W. Daniel , Davis Jeremy S. , Jiggins Francis M. , Wertheim Bregje , Lewis Owen T. , Leips Jeff , Staniczenko Phillip P. A. , Hrcek Jan
Published: February 2021

Molecular identification is increasingly used to speed up biodiversity surveys and laboratory experiments. However, many groups of organisms cannot be reliably identified using standard databases such as GenBank or BOLD due to lack of sequenced voucher specimens identified by experts. Sometimes a large number of sequences are available, but with too many errors to allow identification. Here we address this problem for parasitoids ofDrosophilaby introducing a curated open-access molecular reference database, DROP (Drosophilaparasitoids). IdentifyingDrosophilaparasitoids is challenging and poses a major impediment to realize the full potential of this model system in studies ranging from molecular mechanisms to food webs, and in biological control ofDrosophila suzukii. In DROP (http://doi.org/10.5281/zenodo.4519656), genetic data are linked to voucher specimens and, where possible, the voucher specimens are identified by taxonomists and vetted through direct comparison with primary type material. To initiate DROP, we curated 154 laboratory strains, 856 vouchers, 554 DNA sequences, 16 genomes, 14 transcriptomes, and 6 proteomes drawn from a total of 183 operational taxonomic units (OTUs): 114 describedDrosophilaparasitoid species and 69 provisional species. We found species richness ofDrosophilaparasitoids to be heavily underestimated and provide an updated taxonomic catalogue for the community. DROP offers accurate molecular identification and improves cross-referencing between individual studies that we hope will catalyze research on this diverse and fascinating model system. Our effort should also serve as an example for researchers facing similar molecular identification problems in other groups of organisms.
Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates
Authors: Arunachalam Prabhu S. , Walls Alexandra C. , Golden Nadia , Atyeo Caroline , Fischinger Stephanie , Li Chunfeng , Aye Pyone , Navarro Mary Jane , Lai Lilin , Edara Venkata Viswanadh , Röltgen Katharina , Rogers Kenneth , Shirreff Lisa , Ferrell Douglas E , Wrenn Samuel , Pettie Deleah , Kraft John C. , Miranda Marcos C. , Kepl Elizabeth , Sydeman Claire , Brunette Natalie , Murphy Michael , Fiala Brooke , Carter Lauren , White Alexander G , Trisal Meera , Hsieh Ching-Lin , Russell-Lodrigue Kasi , Monjure Christopher , Dufour Jason , Doyle-Meyer Lara , Bohm Rudolph B. , Maness Nicholas J. , Roy Chad , Plante Jessica A. , Plante Kenneth S. , Zhu Alex , Gorman Matthew J. , Shin Sally , Shen Xiaoying , Fontenot Jane , Gupta Shakti , O’Hagan Derek T. , Most Robbert Van Der , Rappuoli Rino , Coffman Robert L. , Novack David , McLellan Jason S. , Subramaniam Shankar , Montefiori David , Boyd Scott D. , Flynn JoAnne L. , Alter Galit , Villinger Francois , Kleanthous Harry , Rappaport Jay , Suthar Mehul , King Neil P. , Veesler David , Pulendran Bali
Published: February 2021

The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.
Automated in vivo tracking of cortical oligodendrocytes
Authors: Xu Yu Kang T. , Call Cody L. , Sulam Jeremias , Bergles Dwight E.
Published: February 2021

Oligodendrocytes exert a profound influence on neural circuits by accelerating axon potential conduction, altering excitability and providing metabolic support. As oligodendrogenesis continues in the adult brain and is essential for myelin repair, uncovering the factors that control their dynamics is necessary to understand the consequences of adaptive myelination and develop new strategies to enhance remyelination in diseases such as multiple sclerosis. Unfortunately, few methods exist for analysis of oligodendrocyte dynamics, and even fewer are suitable forin vivoinvestigation. Here, we describe the development of a fully automated cell tracking pipeline using convolutional neural networks (Oligo-Track) that provides rapid volumetric segmentation and tracking of thousands of cells over weeksin vivo. This system reliably replicated human analysis, outperformed traditional analytic approaches, and extracted injury and repair dynamics at multiple cortical depths, establishing that oligodendrogenesis after cuprizone-mediated demyelination is suppressed in deeper cortical layers. Volumetric data provided by this analysis revealed that oligodendrocyte soma size progressively decreases after their generation, and declines further prior to death, providing a means to predict cell age and eventual cell death from individual time points. This new CNN-based analysis pipeline offers a rapid, robust method to quantitatively analyze oligodendrocyte dynamicsin vivo, which will aid in understanding how changes in these myelinating cells influence circuit function and recovery from injury and disease.
Revealing the Physiological Origin of Event-Related Potentials using Electrocorticography in Humans
Authors: Cho Hohyun , Schalk Gerwin , Adamek Markus , Moheimanian Ladan , Coon William G. , Jun Sung Chan , Wolpaw Jonathan R. , Brunner Peter
Published: February 2021

The scientific and clinical value of event-related potentials (ERPs) depends on understanding the contributions to them of three possible mechanisms: (1) additivity of time-locked voltage changes; (2) phase resetting of ongoing oscillations; (3) asymmetrical oscillatory activity. Their relative contributions are currently uncertain. This study uses analysis of human electrocorticographic activity to quantify the origins of movement-related potentials (MRPs) and auditory evoked potentials (AEPs). The results show that MRPs are generated primarily by endogenous additivity (88%). In contrast, P1 and N1 components of AEPs are generated almost entirely by exogenous phase reset (93%). Oscillatory asymmetry contributes very little. By clarifying ERP mechanisms, these results enable creation of ERP models; and they enhance the value of ERPs for understanding the genesis of normal and abnormal auditory or sensorimotor behaviors.
FORUM: Building a Knowledge Graph from public databases and scientific literature to extract associations between chemicals and diseases
Authors: Delmas M. , Filangi O. , Paulhe N. , Vinson F. , Duperier C. , Garrier W. , Saunier P.-E. , Pitarch Y. , Jourdan F. , Giacomoni F. , Frainay C.
Published: February 2021

Metabolomics studies aim at reporting a metabolic signature (list of metabolites) related to a particular experimental condition. These signatures are instrumental in the identification of biomarkers or classification of individuals, however their biological and physiological interpretation remains a challenge. Overcoming this challenge is critical when aiming to associate metabolic signatures with potential pathological outcomes. To support this task, we introduce FORUM: a Knowledge Graph (KG) providing a semantic representation of relations between chemicals and biomedical concepts, built from a federation of life science databases and scientific literature repositories. An important number of scientific articles discuss relations between chemical compounds and biomedical concepts in various contexts, from biomarkers to therapeutic uses. The extraction of these statements and their interconnection in a graph structure can thus allow us to identify and explore relations strongly supported in the scientific literature.

The use of a Semantic Web framework on biological data allows us to apply ontological based reasoning to infer new relations between entities. We show that these new relations provide different levels of abstraction and could open the path to new hypotheses. We estimate the statistical relevance of each extracted relation, explicit or inferred, using an enrichment analysis, and instantiate them as new knowledge in the KG to support results interpretation/further inquiries. Beyond this result, FORUM can also provide insights into complex biological questions and the extracted information could then be used for further developments.

Containing more than 8 billion triples and providing more than 8 million relations, FORUM leverages the increasing availability of linked datasets in life science and is built in agreement with FAIR principles. A web interface to browse and download the extracted relations, as well as a SPARQL endpoint to directly probe the whole FORUM knowledge graph, are available athttps://forum-webapp.semantic-metabolomics.fr. The code needed to reproduce the triplestore is available athttps://github.com/eMetaboHUB/Forum-DiseasesChem.
Structural origins of protein conformational entropy
Authors: Caro José A. , Valentine Kathleen G. , Wand A. Joshua
Published: February 2021

The thermodynamics of molecular recognition by proteins is a central determinant of complex biochemistry. For over a half-century detailed cryogenic structures have provided deep insight into the energetic contributions to ligand binding by proteins1. More recently, a dynamical proxy based on NMR-relaxation methods has revealed an unexpected richness in the contributions of conformational entropy to the thermodynamics of ligand binding2,3,4,5. There remains, however, a discomforting absence of an understanding of the structural origins of fast internal motion and the conformational entropy that this motion represents. Here we report the pressure-dependence of fast internal motion within the ribonuclease barnase and its complex with the protein barstar. Distinctive clustering of the pressure sensitivity correlates with the presence of small packing defects or voids surrounding affected side chains. Prompted by this observation, we performed an analysis of the voids surrounding over 2,500 methyl-bearing side chains having experimentally determined order parameters. We find that changes in unoccupied volume as small as a single water molecule surrounding buried side chains greatly affects motion on the subnanosecond timescale. The discovered relationship begins to permit construction of a united view of the relationship between changes in the internal energy, as exposed by detailed structural analysis, and the conformational entropy, as represented by fast internal motion, in the thermodynamics of protein function.
Environmental enrichment mitigates stroke-induced change in sharp-wave associated ripple characteristics
Authors: Ip Zachary , Rabiller Gratianne , He Ji-Wei , Chavan Shivalika , Nishijima Yasuo , Akamatsu Yosuke , Liu Jialing , Yazdan-Shahmorad Azadeh
Published: February 2021

Cognitive and memory impairments are common sequelae after stroke, yet how middle cerebral artery (MCA) stroke chronically affects the neural activity of the hippocampus, a brain region critical for memory but remote from the stroke epicenter, is poorly understood. Environmental enrichment (EE) improves cognition following stroke; however, the electrophysiology that underlies this behavioral intervention is still elusive. We recorded local field potentials simultaneously from sensorimotor cortex and hippocampus in rats following MCA occlusion and subsequent EE treatment. We found that MCA stroke significantly impacted the electrophysiology in the hippocampus, in particular it disrupted characteristics of sharp-wave associated ripples (SPW-Rs) which are known correlates of memory and cognition. Importantly, we show that EE mitigates stroke-induced changes to SPW-R characteristics. These results begin to uncover the complex interaction between cognitive deficit following stroke and EE treatment, providing a testbed to assess different strategies for therapeutics following stroke.
Rapid evolution of complete dosage compensation inPoecilia
Authors: Metzger David C.H. , Sandkam Benjamin A. , Darolti Iulia , Mank Judith E.
Published: February 2021

Dosage compensation balances gene expression between the sexes in systems with diverged heterogametic sex chromosomes. Theory predicts that dosage compensation should rapidly evolve in parallel with the divergence of sex chromosomes to prevent the deleterious effects of dosage imbalances that occur as a result of sex chromosome divergence. Examples of complete dosage compensation, where gene expression of the entire sex chromosome is compensated, are rare and have only been found in relatively ancient sex chromosome systems. Consequently, very little is known about the evolutionary dynamics of complete dosage compensation systems. We recently found the first example of complete dosage compensation in a fish,Poecilia picta. We also found that the Y chromosome degraded substantially in the common ancestor ofP. pictaand their close relativePoecilia parae. In this study we find thatP. paraealso have complete dosage compensation, thus complete dosage compensation likely evolved in the short (∼3.7 my) interval after the split of the ancestor of these two species fromP. reticulata, but before they diverged from each other. These data suggest that novel dosage compensation mechanisms can evolve rapidly, thus supporting the longstanding theoretical prediction that such mechanisms arise in parallel with rapidly diverging sex chromosomes.

SIGNIFICANCE STATEMENT

In species with XY sex chromosomes, females (XX) have as many copies of X-linked genes compared to males (XY), leading to unbalanced expression between the sexes. Theory predicts that dosage compensation mechanisms should evolve rapidly as X and Y chromosomes diverge, but examples of complete dosage compensation in recently diverged sex chromosomes are scarce, making this theory difficult to test. Across Poeciliid species the X and Y chromosomes have recently diversified. Here we find complete dosage compensation evolved rapidly as the X and Y diverged in the common ancestor ofPoecilia paraeandP. picta, supporting that novel dosage compensation mechanisms can evolve rapidly in tandem with diverging sex chromosomes. These data confirm longstanding theoretical predictions of sex chromosome evolution.
Remarked Suppression of Aβ42 Protomer-Protomer Dissociation Reaction Elucidated by Molecular Dynamics Simulation
Authors: Kurisaki Ikuo , Tanaka Shigenori
Published: February 2021

Multimeric protein complexes are molecular apparatuses to regulate biological systems and often determine their fate. Among proteins forming such molecular assemblies, amyloid proteins have drawn attention over a half-century since amyloid fibril formation of these proteins is supposed to be a common pathogenic cause for neurodegenerative diseases. This process is triggered by the accumulation of fibril-like aggregates, while the microscopic mechanisms are mostly elusive due to technical limitation of experimental methodologies in individually observing each of diverse aggregate species in the aqueous solution. We then addressed this problem by employing atomistic molecular dynamics simulations for the paradigmatic amyloid protein, amyloid-β (1-42) (Aβ42). Seven different dimeric forms of oligomeric Aβ42 fibril-like aggregate in aqueous solution, ranging from tetramer to decamer, were considered. We found additive effects of the size of these fibril-like aggregates on their thermodynamic stability and have clarified kinetic suppression of protomer-protomer dissociation reactions at and beyond the point of pentamer dimer formation. This observation was obtained from the specific combination of the Aβ42 protomer structure and the physicochemical condition that we here examined, while it is worthwhile to recall that several amyloid fibrils take dimeric forms of their protomers. We could thus conclude that the stable formation of fibril-like protomer dimer should be involved in a turning point where rapid growth of amyloid fibrils is triggered.
PolyA: a tool for adjudicating competing annotations of biological sequences
Authors: Carey Kaitlin M. , Hubley Robert , Lesica George T. , Olson Daniel , Roddy Jack W. , Rosen Jeb , Shingleton Audrey , Smit Arian F. , Wheeler Travis J.
Published: February 2021

Annotation of a biological sequence is usually performed by aligning that sequence to a database of known sequence elements. When that database contains elements that are highly similar to each other, the proper annotation may be ambiguous, because several entries in the database produce high-scoring alignments. Typical annotation methods work by assigning a label based on the candidate annotation with the highest alignment score; this can overstate annotation certainty, mislabel boundaries, and fails to identify large scale rearrangements or insertions within the annotated sequence. Here, we present a new software tool, PolyA, that adjudicates between competing alignment-based annotations by computing estimates of annotation confidence, identifying a trace with maximal confidence, and recursively splicing/stitching inserted elements. PolyA communicates annotation certainty, identifies large scale rearrangements, and detects boundaries between neighboring elements.
Clinically Validated Model Predicts the Effect of Intratumoral Heterogeneity on Overall Survival for Non-Small Cell Lung Cancer (NSCLC) Patients
Authors: Ghaderi Nima , Jung Joseph H. , Odde David J. , Peacock Jeffrey
Published: February 2021

Purpose

We demonstrate the importance of considering intratumoral heterogeneity and the development of resistance during fractionated radiotherapy when the same dose of radiation is delivered for all fractions (Fractional Equivalent Dosing FED).

Materials and Methods

A mathematical model was developed with the following parameters: a starting population of 1011non-small cell lung cancer (NSCLC) tumor cells, 48-hour doubling time, and cell death per the linear-quadratic (LQ) model with α and β values derived from RSIα/β, in a previously described gene expression based model that estimates α and β. To incorporate both inter- and intratumor radiation sensitivity, RSIα/β output for each patient sample is assumed to represent an average value in a gamma distribution with the bounds set to -50% and +50% of RSIα/b. Therefore, we assume that within a given tumor there are subpopulations that have varying radiation sensitivity parameters that are distinct from other tumor samples with a different mean RSIα/β. A simulation cohort (SC) comprised of 100 lung cancer patients with available RSIα/β (patient specific α and β values) was used to investigate 60Gy in 30 fractions with fractionally equivalent dosing (FED). A separate validation cohort (VC) of 57 lung cancer patients treated with radiation with available local control (LC), overall survival (OS), and tumor gene expression was used to clinically validate the model. Cox regression was used to test for significance to predict clinical outcomes as a continuous variable in multivariate analysis (MVA). Finally, the VC was used to compare FED schedules with various altered fractionation schema utilizing a Kruskal-Wallis test. This was examined using the end points of end of treatment log cell count (LCC) and by a parameter described as mean log kill efficiency (LKE) defined as:

Results

Cox regression analysis on LCC for the VC demonstrates that, after incorporation of intratumoral heterogeneity, LCC has a linear correlation with local control (p = 0.002) and overall survival (p =< 0.001). Other suggested treatment schedules labeled as High Intensity Treatment (HIT) with a total 60Gy delivered over 6 weeks have a lower mean LCC and an increased LKE compared to standard of care 60Gy delivered in FED in the VC.

Conclusion

We find that LCC is a clinically relevant metric that is correlated with local control and overall survival in NSCLC. We conclude that 60Gy delivered over 6 weeks with altered HIT fractionation leads to an enhancement in tumor control compared to FED when intratumoral heterogeneity is considered.
Effect of cellular rearrangement time delays on the rheology of vertex models for confluent tissues
Authors: Erdemci-Tandogan Gonca , Manning M. Lisa
Published: February 2021

Large-scale tissue deformation during biological processes such as morphogenesis requires cellular rearrangements. The simplest rearrangement in confluent cellular monolayers involves neighbor exchanges among four cells, called a T1 transition, in analogy to foams. But unlike foams, cells must execute a sequence of molecular processes, such as endocytosis of adhesion molecules, to complete a T1 transition. Such processes could take a long time compared to other timescales in the tissue. In this work, we incorporate this idea by augmenting vertex models to require a fixed, finite time for T1 transitions, which we call the “T1 delay time”. We study how variations in T1 delay time affect tissue mechanics, by quantifying the relaxation time of tissues in the presence of T1 delays and comparing that to the cell-shape based timescale that characterizes fluidity in the absence of any T1 delays. We show that the molecular-scale T1 delay timescale dominates over the cell shape-scale collective response timescale when the T1 delay time is the larger of the two. We extend this analysis to tissues that become anisotropic under convergent extension, finding similar results. Moreover, we find that increasing the T1 delay time increases the percentage of higher-fold coordinated vertices and rosettes, and decreases the overall number of successful T1s, contributing to a more elastic-like – and less fluid-like – tissue response. Our work suggests that molecular mechanisms that act as a brake on T1 transitions could stiffen global tissue mechanics and enhance rosette formation during morphogenesis.
Nano-hydroxyapatite coating synthesized on quasi-fibrillar superstructures of collagen hydrolysate leads to superior osteoblast proliferation when compared to nano-hydroxyapatite synthesized on collagen fibrils
Authors: Banerjee Pradipta , Bajaj Mayur , Bhat Chetna , Geethika Y , Irle Hemanth
Published: February 2021

This study had a two-fold objective: To utilize collagen hydrolysate for synthesizing a nanoscale Hydroxyapatite (HA) coating that would act as a superior osteoblast adhesion/proliferation agent compared to collagen-derived HA (C/HA) and to comprehend the significant role played by structural constraints on HA nucleation. Collagen was extracted from pacu skin with a high yield of 65.3% (w/w of tissue). It was digested by collagenase and the hydrolysate (CH) was purified with a high yield of 0.68g/g of collagen. The CH peptides had a mass of 6kDa, a predominant PP-II conformation and formed self-assembling hierarchical structures at physiological pH with dimensions of 842.2±229nm. The HA synthesized on CH (CH/HA) displayed higher yield when compared to C/HA. Structural analysis of CH/HA revealed that the PP-II peptides coiled to form mimic-helical moieties with reduced intermolecular packing distance of 0.9nm. The mimic helices cross-linked to form a vast quasi-fibrillar network that was comparatively smaller than collagen fibrils but exhibited enhanced stability and greater dynamicity. CH/HA displayed intense calcium-carboxyl interactions, sharper diffraction planes, smaller size of 48±6.2nm and a Ca/P ratio closer to 1.69 when compared to C/HA along with displaying serrated edge blooming crystals. Because of the small size, the CH/HA nanocrystals displayed significantly better osteoblast adhesion than C/HA and reduced the doubling time of cells. Overall, the results indicated that CH based nanocomposites displayed suitable morphological characteristics and cellular response for potential application as implant and bone graft coating material.

Graphical abstract
Genomes of gut bacteria fromNasoniawasps shed light on phylosymbiosis and microbe-assisted hybrid breakdown
Authors: Cross Karissa L. , Leigh Brittany A. , Hatmaker E. Anne , Mikaelyan Aram , Miller Asia K. , Bordenstein Seth R.
Published: February 2021

Phylosymbiosis is a cross-system trend whereby microbial community relationships recapitulate the host phylogeny. InNasoniaparasitoid wasps, phylosymbiosis occurs throughout development, is distinguishable between sexes, and benefits host development and survival. Moreover, the microbiome shifts in hybrids as a rareProteusbacteria in the microbiome becomes dominant. The larval hybrids then catastrophically succumb to bacterial-assisted lethality and reproductive isolation between the species. Two important questions for understanding phylosymbiosis and bacterial-assisted lethality in hybrids are: (i) Do theNasoniabacterial genomes differ from other animal isolates and (ii) Are the hybrid bacterial genomes the same as those in the parental species? Here we report the cultivation, whole genome sequencing, and comparative analyses of the most abundant gut bacteria inNasonialarvae,Providencia rettgeriandProteus mirabilis. Characterization of new isolates showsProteus mirabilisforms a more robust biofilm thanProvidencia rettgeriand when grown in co-culture,Proteus mirabilissignificantly outcompetesProvidencia rettgeri. Providencia rettgerigenomes fromNasoniaare similar to each other and more divergent to pathogenic, human-associates strains.Proteus mirabilisfromN. vitripennis, N. giraulti, and their hybrid offspring are nearly identical and relatively distinct from human isolates. These results indicate that members of the larval gut microbiome withinNasoniaare most similar to each other, and the strain of the dominantProteus mirabilisin hybrids is resident in parental species. Holobiont interactions between shared, resident members of the wasp microbiome and the host underpin phylosymbiosis and hybrid breakdown.

IMPORTANCE

Animal and plant hosts often establish intimate relationships with their microbiomes. In varied environments, closely-related host species share more similar microbiomes, a pattern termed phylosymbiosis. When phylosymbiosis is functionally significant and beneficial, microbial transplants between host species or host hybridization can have detrimental consequences on host biology. In theNasoniaparasitoid wasp genus that contains a phylosymbiotic gut community, both effects occur and provide evidence for selective pressures on the holobiont. Here, we show that bacterial genomes inNasoniadiffer from other environments and harbor genes with unique functions that may regulate phylosymbiotic relationships. Furthermore, the bacteria in hybrids are identical to parental species, thus supporting a hologenomic tenet that the same members of the microbiome and the host genome impact phylosymbiosis, hybrid breakdown, and speciation.
Suppression ofPlasmodiumMIF-CD74 Signaling Protects Against Severe Malaria
Authors: Garcia Alvaro Baeza , Siu Edwin , Du Xin , Leng Lin , Franke-Fayard Blandine , Janse Chris J , Howland Shanshan W , Rénia Laurent , Lolis Elias , Bucala Richard
Published: February 2021

Malaria begins when mosquito-bornePlasmodiumsporozoites invade hepatocytes and usurp host pathways to support the differentiation and multiplication of erythrocyte-infective merozoite progeny. The deadliest complication of infection, cerebral malaria, accounts for the majority of malarial fatalities. Although our understanding of the cellular and molecular mechanisms underlying the pathology remains incomplete, recent studies support the contribution of systemic and neuroinflammation as the cause of cerebral edema and blood-brain barrier (BBB) dysfunction. AllPlasmodiumspecies encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses.PlasmodiumMIF (PMIF) similarly signals through the host MIF receptor CD74, leading to an enhanced inflammatory response. We investigated the PMIF-CD74 interaction in the onset of experimental cerebral malaria (ECM) using CD74 deficient (Cd74−/−) mice, which were found to be protected from ECM. The protection was associated with the inability of brain microvessels fromCd74−/−hosts to present parasite antigen to sequesteredPlasmodium-specific CD8+T cells. Infection of mice with PMIF-deficient sporozoites (PbAmif-) also protected mice from ECM, highlighting the pivotal role of PMIF in the pre-erythrocytic stage of the infection. A novel pharmacologic PMIF-selective antagonist reduced PMIF/CD74 signaling and fully protected mice from ECM. These findings reveal a conserved mechanism forPlasmodiumusurpation of host CD74 signaling and suggest a tractable approach for new pharmacologic intervention.
Aggregation-induced emission dots assisted non-invasive fluorescence hysterography in near-infrared IIb window
Authors: Yu Xiaoming , Ying Yanyun , Feng Zhe , Qi Ji , Zheng Junyan , Zhang Yuhuang , Liu Juan , Qian Jun , Tang Ben Zhong , Zhang Dan
Published: February 2021

Uterine diseases seriously threaten the physical and mental health of women. The main principle, when clinicians adopt examinations, is to achieve efficient diagnosis without negative effect on the physical function including fertility. Hysterography in near-infrared (NIR) IIb window (1500-1700 nm) presents perceptibly enhanced signal to background ratio (SBR) and higher penetration capability compared with those beyond 1000 nm and 1300 nm, but lays down high requirements for the biosafety of fluorophores at the same time. Assisted by the biologically excretable aggregation-induced emission (AIE) dots, non-invasive NIR-IIb fluorescence hysterography visualized typical Y-shaped uteruses, real-time uterine peristalsis or the uterine lesions (mimetic disease statuses in clinic) in mouse models. Significantly, after intrauterine perfusion, the reproductive capacity was unimpaired via fertility assessment and histological analysis. This work could inspire some new ideas for non-invasive clinical diagnosis of uterine diseases and effectively promote the clinical translation of AIE dots.
Mutation N501Y in RBD of Spike Protein Strengthens the Interaction between COVID-19 and its Receptor ACE2
Authors: Tian Fang , Tong Bei , Sun Liang , Shi Shengchao , Zheng Bin , Wang Zibin , Dong Xianchi , Zheng Peng
Published: February 2021

SARS-CoV-2 is spreading around the world for the past year. Enormous efforts have been taken to understand its mechanism of transmission. It is well established now that the receptor-binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) as its first step of entry. Being a single-stranded RNA virus, SARS-CoV-2 is evolving rapidly. Recently, several variants such as B.1.1.7, B.1.351, and P.1, with a key mutation N501Y on the RBD, appear to be more infectious to humans. To understand its mechanism, we combined cell surface binding assay, kinetics study, single-molecule technique, and computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction characterized from all these methodologies, while the other two mutations from B.1.351 contributed to a less effect. Fluorescence-activated cell scan (FACS) assays found that RBD N501Y mutations are of higher binding affinity to ACE2 than the wild type. Surface plasmon resonance further indicated that N501Y mutation had a faster association rate and slower dissociation rate. Consistent with the kinetics study, atomic force microscopy-based single-molecule force microscopy quantify their strength on living cells, showing a higher binding probability and unbinding force for the mutation. Finally, Steered Molecular Dynamics (SMD) simulations on the dissociation of RBD-ACE2 complexes revealed that the N501Y introduced additional π-π and π-cation interaction for the higher force/interaction. Taken together, we suggested that the reinforced interaction from N501Y mutation in RBD should play an essential role in the higher transmission of COVID-19 variants.
Female and maleSirex noctiliouse age and size to select a mate
Authors: Queffelec Joséphine , Allison Jeremy D. , Slippers Bernard , Greeff Jaco M.
Published: February 2021

While male mate choice in insects is a widely accepted concept, there is still limited evidence showing that lek formation is compatible with the evolution of male mate choice. In the woodwaspSirex noctilio, males form leks that are used by females to select a mate. However, males have been observed to ignore certain females, suggesting the presence of male mate choice despite the presence of a lek mating system. In this study we demonstrate that males only attempt to mate with certain females. To understand the criteria used by males and females to select a mate, we also tested the effect of age, size, and male to female size ratio on the number of mating attempts made by males and on female receptivity. We demonstrate that size and age play a role in both male and female mate choice. Our results suggest that males must reach sexual maturity after emergence and are neither receptive nor attractive to females during the first few days of their lives. We also show that older females become less attractive to males, suggesting that femaleS. noctilioswitch to a strict host location phase sometime after emergence. Our results show that male and female size, and the ratio between them, play a role in mate choice. While larger males are more motivated to mate, their large size can physically prevent them from mating with small females. Small females are also more attractive and more receptive to males, consistent with the presence of convenience polyandry inS. noctilio.
The Kinetic Landscape of Nucleosome Assembly: A Coarse-Grained Molecular Dynamics Study
Authors: Brandani Giovanni B. , Tan Cheng , Takada Shoji
Published: February 2021

The organization of nucleosomes along the Eukaryotic genome is maintained over time despite disruptive events such as replication. During this complex process, histones and DNA can form a variety of non-canonical nucleosome conformations, but their precise molecular details and roles during nucleosome assembly remain unclear. In this study, employing coarse-grained molecular dynamics simulations and Markov state modeling, we characterized the complete kinetics of nucleosome assembly. On the nucleosome-positioning 601 DNA sequence, we observe a rich transition network among various canonical and non-canonical tetrasome, hexasome, and nucleosome conformations. A low salt environment makes nucleosomes stable, but the kinetic landscape becomes more rugged, so that the system is more likely to be trapped in off-pathway partially assembled intermediates. We find that the co-operativity between DNA bending and histone association enables positioning sequence motifs to direct the assembly process, with potential implications for the dynamic organization of nucleosomes on real genomic sequences.
Optical activation of TrkB neurotrophin receptor in mouse ventral hippocampus promotes plasticity and facilitates fear extinction
Authors: Umemori Juzoh , Didio Giuliano , Winkel Frederike , Pou Maria Llach , Harkki Juliana , Russo Giacomo Lo , Verie Maarten , Antila Hanna , Buj Chloe , Taira Tomi , Lauri Sari E. , Guirado Ramon , Castrén Eero
Published: February 2021

Successful extinction of traumatic memories depends on neuronal plasticity in the fear extinction network. However, the mechanisms involved in the extinction process remain poorly understood. Here, we investigated the fear extinction network by using a new optogenetic technique that allows temporal and spatial control of neuronal plasticityin vivo. We optimized an optically inducible TrkB (CKII-optoTrkB), the receptor of the brain-derived neurotrophic factor, which can be activated upon blue light exposure to increase plasticity specifically in pyramidal neurons. The activation of CKII-optoTrkB facilitated the induction of LTP in Schaffer collateral-CA1 synapses after brief theta-burst stimulation and increased the expression of FosB in the pyramidal neurons of the ventral hippocampus, indicating enhanced plasticity in that brain area. We showed that optical stimulation of the CA1 region of the ventral hippocampus during fear extinction training led to an attenuated conditioned fear memory. This was a specific effect only observed when combining extinction training with CKII-optoTrkB activation, and not when using either intervention alone. Thus, TrkB activation in ventral CA1 pyramidal neurons promotes a state of neuronal plasticity that allows extinction training to guide neuronal network remodeling to overcome fear memories. Our methodology is a powerful tool to induce neuronal network remodeling in the adult brain, and can attenuate neuropsychiatric symptoms caused by malfunctioning networks.
ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibitsin vivoefficacy in a Syrian Hamster model
Authors: Vandyck Koen , Abdelnabi Rana , Gupta Kusum , Jochmans Dirk , Jekle Andreas , Deval Jerome , Misner Dinah , Bardiot Dorothée , Foo Caroline S. , Liu Cheng , Ren Suping , Beigelman Leonid , Blatt Lawrence M. , Boland Sandro , Vangeel Laura , Dejonghe Steven , Chaltin Patrick , Marchand Arnaud , Serebryany Vladimir , Stoycheva Antitsa , Chanda Sushmita , Symons Julian A. , Raboisson Pierre , Neyts Johan
Published: February 2021

There is an urgent need for antivirals targeting the SARS-CoV-2 virus to fight the current COVID-19 pandemic. The SARS-CoV-2 main protease (3CLpro) represents a promising target for antiviral therapy. The lack of selectivity for some of the reported 3CLpro inhibitors, specifically versus cathepsin L, raises potential safety and efficacy concerns. ALG-097111 potently inhibited SARS-CoV-2 3CLpro (IC50= 7 nM) without affecting the activity of human cathepsin L (IC50> 10 μM). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log10(RNA copies/mg) reduction of the viral RNA copies and 3.7 log10(TCID50/mg) reduction in the infectious virus titers in the lungs was observed. These results provide the first in vivo validation for the SARS-CoV-2 3CLpro as a promising therapeutic target for selective small molecule inhibitors.
Ongoing habenular activity is driven by forebrain networks and modulated by olfactory stimuli
Authors: Bartoszek Ewelina Magdalena , Jetti Suresh Kumar , Chau Khac Thanh Phong , Yaksi Emre
Published: February 2021

Ongoing neural activity, which represents internal brain states, is constantly modulated by the sensory information that is generated by the environment. In this study, we show that the habenular circuits act as a major brain hub integrating the structured ongoing activity of the limbic forebrain circuitry and the olfactory information. We demonstrate that ancestral homologs of amygdala and hippocampus in zebrafish forebrain are the major drivers of ongoing habenular activity. We also reveal that odor stimuli can modulate the activity of specific habenular neurons that are driven by this forebrain circuitry. Our results highlight a major role for the olfactory system in regulating the ongoing activity of the habenula and the forebrain, thereby altering brain’s internal states.