bluuebunny/crossref_metadata_2025 huggingface dataset:
AgAnt: A computational tool to assess Agonist/Antagonist mode of interaction
Authors: Aggarwal Bhavay , Ray Arjun
Published: November 2021

Activity modulation of proteins is an essential biochemical process in cell. The interplay of the protein, as receptor, and it’s corresponding ligand dictates the functional effect. An agonist molecule when bound to a receptor produces a response within the cell while an antagonist will block the binding site/produce the opposite effect of that of an agonist. Complexity grows with scenarios where some ligands might act as an agonist in certain conditions while as an antagonist in others [1, 3]. It is imperative to decipher the receptor-ligand functional effect for understanding native biochemical processes as well as for drug discovery. Experimental activity determination is a time extensive process and computational solution towards prediction of activity specific to the receptor-ligand interaction would be of wide interest.
Subiculum – BNST Structural Connectivity in Humans and Macaques
Authors: Berry Samuel C. , Lawrence Andrew D. , Lancaster Thomas M. , Casella Chiara M. , Aggleton John P. , Postans Mark
Published: November 2021

Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily mediated through the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts are moderately heritable (h2 ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. We did, however, find subiculum complex-BNST tract microstructure associations with BMI, age, and sex. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.
Gene drives and population persistence vs elimination: the impact of spatial structure and inbreeding at low density
Authors: Beaghton PJ , Burt Austin
Published: November 2021

Synthetic gene drive constructs are being developed to control disease vectors, invasive species, and other pest species. In a well-mixed random mating population a sufficiently strong gene drive is expected to eliminate a target population, but it is not clear whether the same is true when spatial processes play a role. In species with an appropriate biology it is possible that drive-induced reductions in density might lead to increased inbreeding, reducing the efficacy of drive, eventually leading to suppression rather than elimination, regardless of how strong the drive is. To investigate this question we analyse a series of explicitly solvable stochastic models considering a range of scenarios for the relative timing of mating, reproduction, and dispersal and analyse the impact of two different types of gene drive, a Driving Y chromosome and a homing construct targeting an essential gene. We find in all cases a sufficiently strong Driving Y will go to fixation and the population will be eliminated, except in the one life history scenario (reproduction and mating in patches followed by dispersal) where low density leads to increased inbreeding, in which case the population persists indefinitely, tending to either a stable equilibrium or a limit cycle. These dynamics arise because Driving Y males have reduced mating success, particularly at low densities, due to having fewer sisters to mate with. Increased inbreeding at low densities can also prevent a homing construct from eliminating a population. For both types of drive, if there is strong inbreeding depression, then the population cannot be rescued by inbreeding and it is eliminated. These results highlight the potentially critical role that low-density-induced inbreeding and inbreeding depression (and, by extension, other sources of Allee effects) can have on the eventual impact of a gene drive on a target population.
The structural determinants of intra-protein compensatory substitutions
Authors: Chaurasia Shilpi , Dutheil Julien Y.
Published: November 2021

Compensating substitutions happen when one mutation is advantageously selected because it restores the loss of fitness induced by a previous deleterious mutation. How frequent such mutations occur in evolution and what is the structural and functional context permitting their emergence remain open questions. We built an atlas of intra-protein compensatory substitutions using a phylogenetic approach and a dataset of 1,630 bacterial protein families for which high-quality sequence alignments and experimentally derived protein structures were available. We identified more than 51,000 positions coevolving by the mean of predicted compensatory mutations. Using the evolutionary and structural properties of the analyzed positions, we demonstrate that compensatory mutations are scarce (typically only a few in the protein history) but widespread (the majority of proteins experienced at least one). Typical coevolving residues are evolving slowly, are located in the protein core outside secondary structure motifs, and are more often in contact than expected by chance, even after accounting for their evolutionary rate and solvent exposure. An exception to this general scheme are residues coevolving for charge compensation, which are evolving faster than non-coevolving sites, in contradiction with predictions from simple coevolutionary models, but similar to stem pairs in RNA. While sites with a significant pattern of coevolution by compensatory mutations are rare, the comparative analysis of hundreds of structures ultimately permits a better understanding of the link between the three-dimensional structure of a protein and its fitness landscape.
Differential regulation of degradation and immune pathways underlies adaptation of the ectosymbiotic nematodeLaxus oneistusto oxic-anoxic interfaces
Authors: Paredes Gabriela F. , Viehboeck Tobias , Markert Stephanie , Mausz Michaela A. , Sato Yui , Liebeke Manuel , König Lena , Bulgheresi Silvia
Published: November 2021

Eukaryotes may experience oxygen deprivation under both physiological and pathological conditions. Because oxygen shortage leads to a reduction in cellular energy production, all eukaryotes studied so far conserve energy by suppressing their metabolism. However, the molecular physiology of animals that naturally and repeatedly experience anoxia is underexplored. One such animal is the marine nematodeLaxus oneistus. It thrives, invariably coated by its sulfur-oxidizing symbiontCandidatusThiosymbion oneisti, in anoxic sulfidic or hypoxic sand. Here, transcriptomics and proteomics showed that, whether in anoxia or not,L. oneistusmostly expressed genes involved in ubiquitination, energy generation, oxidative stress response, immune response, development, and translation. Importantly, ubiquitination genes were also upregulated when the nematode was subjected to anoxic sulfidic conditions, together with genes involved in autophagy, detoxification and ribosome biogenesis. We hypothesize that these degradation pathways were induced to recycle damaged cellular components (mitochondria) and misfolded proteins into nutrients. Remarkably, whenL. oneistuswas subjected to anoxic sulfidic conditions, lectin and mucin genes were also upregulated, potentially to promote the attachment of its thiotrophic symbiont. Furthermore, the nematode appeared to survive oxygen deprivation by using an alternative electron carrier (rhodoquinone) and acceptor (fumarate), to rewire the electron transfer chain. On the other hand, under hypoxia, genes involved in costly processes (e.g., amino acid biosynthesis, development, feeding, mating) were upregulated, together with the worm’s Toll- like innate immunity pathway and several immune effectors (e.g., Bacterial Permeability Increasing proteins, fungicides).

In conclusion, we hypothesize that, in anoxic sulfidic sand,L. oneistusupregulates degradation processes, rewires oxidative phosphorylation and by reinforces its coat of bacterial sulfur-oxidizers. In upper sand layers, instead, it appears to produce broad-range antimicrobials and to exploit oxygen for biosynthesis and development.
Three-dimensional Multicolor Subcellular Imaging by Fast Serial Sectioning Tomography for Centimeter-scale Specimens
Authors: Yu Wentao , Kang Lei , Tsang Victor T. C. , Zhang Yan , Wong Ivy H. M. , Wong Terence T. W.
Published: November 2021

Rapid multicolor three-dimensional (3D) imaging for centimeter-scale specimens with subcellular resolution remains a challenging but captivating scientific pursuit. Here, we present a fast, automated, cost-effective, and versatile multicolor 3D imaging method with ultraviolet (UV) surface excitation and vibratomy-assisted sectioning, termed translational rapid ultraviolet-excited sectioning tomography (TRUST). TRUST enables exogenous molecular-specific fluorescence and endogenous content-rich autofluorescence imaging simultaneously with the help of a UV light-emitting diode and a color camera. Commonly applied tissue preparation procedures (e.g., staining or clearing) are laborious, time-consuming, and may induce detrimental effects on processed samples. In TRUST, formalin-fixed specimens are stained with real-time double labeling layer by layer along with serial widefield optical illumination with raster scanning and mechanical sectioning to improve the staining speed and reveal rich biological information. All vital organs in mice have been imaged by TRUST to demonstrate its fast, robust, and high-content multicolor 3D imaging ability. Moreover, its potential for developmental biology has also been validated by imaging entire mouse embryos (taking ∼2 days for imaging the embryo at the embryonic day of 15). TRUST offers a way for multicontrast and multicolor whole-organ 3D imaging with high resolution and high speed while relieving researchers from heavy sample preparation workload.
Autonomous treatment of bacterial infections in vivo using antimicrobial micro- and nanomachines
Authors: Arqué Xavier , Torres Marcelo D. T. , Patiño Tania , Boaro Andreia , Sánchez Samuel , de la Fuente-Nunez Cesar
Published: November 2021

The increasing resistance of bacteria to existing antibiotics constitutes a major public health threat globally. Most current antibiotic treatments are hindered by poor delivery to the infection site, leading to undesired off-target effects and drug resistance development and spread. Here, we describe micro- and nanomachines that effectively and autonomously deliver antibiotic payloads to the target area. The active motion and antimicrobial activity of the silica-based robots are driven by catalysis of the enzyme urease and antimicrobial peptides, respectively. These antimicrobial machines show micromolar bactericidal activity in vitro against different Gram-positive and Gram-negative pathogenic bacterial strains and act by rapidly depolarizing their membrane. Finally, they demonstrated autonomous anti-infective efficacy in vivo in a clinically relevant abscess infection mouse model. In summary, our machines combine navigation, catalytic conversion, and bactericidal capacity to deliver antimicrobial payloads to specific infection sites. This technology represents a much-needed tool to direct therapeutics to their target to help combat drug-resistant infections.
An evaluation of resonant scanning as a high-speed imaging technique for two-photon imaging of cortical vasculature
Authors: Zhou Annie , Engelmann Shaun A. , Mihelic Samuel A. , Tomar Alankrit , Hassan Ahmed M. , Dunn Andrew K.
Published: November 2021

We demonstrate a simple, low-cost two-photon microscope design with both galvo-galvo and resonant-galvo scanning capabilities. We quantify and compare the signal-to-noise ratios and imaging speeds of the galvo-galvo and resonant-galvo scanning modes when used for murine neurovascular imaging. The two scanning modes perform as expected under shot-noise limited detection and are found to achieve comparable signal-to-noise ratios. Resonant-galvo scanning is capable of reaching desired signal-to-noise ratios using less acquisition time when higher excitation power can be used. Given equal excitation power and total pixel dwell time between the two methods, galvo-galvo scanning outperforms resonant-galvo scanning in image quality when detection deviates from being shot-noise limited.
Genome assembly of the Australian black tiger shrimp (Penaeus monodon) reveals a fragmented IHHNV EVE sequence
Authors: Huerlimann Roger , Cowley Jeff A , Wade Nicholas M , Wang Yinan , Kasinadhuni Naga , Chan Chon-Kit Kenneth , Jabbari Jafar , Siemering Kirby , Gordon Lavinia , Tinning Matthew , Montenegro Juan D , Maes Gregory E , Sellars Melony J , Coman Greg J , McWilliam Sean , Zenger Kyall R , Khatkar Mehar S , Raadsma Herman W , Donovan Dallas , Krishna Gopala , Jerry Dean R
Published: November 2021

Shrimp are a valuable aquaculture species globally; however, disease remains a major hindrance to shrimp aquaculture sustainability and growth. Mechanisms mediated by endogenous viral elements (EVEs) have been proposed as a means by which shrimp that encounter a new virus start to accommodate rather than succumb to infection over time. However, evidence on the nature of such EVEs and how they mediate viral accommodation is limited. More extensive genomic data on Penaeid shrimp from different geographical locations should assist in exposing the diversity of EVEs. In this context, reported here is a PacBio Sequel-based draft genome assembly of an Australian black tiger shrimp (Penaeus monodon) inbred for one generation. The 1.89 Gbp draft genome is comprised of 31,922 scaffolds (N50: 496,398 bp) covering 85.9% of the projected genome size. The genome repeat content (61.8% with 30% representing simple sequence repeats) is almost the highest identified for any species. The functional annotation identified 35,517 gene models, of which 25,809 were protein-coding and 17,158 were annotated using interproscan. Scaffold scanning for specific EVEs identified an element comprised of a 9,045 bp stretch of repeated, inverted and jumbled genome fragments of Infectious hypodermal and hematopoietic necrosis virus (IHHNV) bounded by a repeated 591/590 bp host sequence. As only near complete linear ~4 kb IHHNV genomes have been found integrated in the genome of P. monodon previously, its discovery has implications regarding the validity of PCR tests designed to specifically detect such linear EVE types. The existence of joined inverted IHHNV genome fragments also provides a means by which hairpin dsRNAs could be expressed and processed by the shrimp RNA interference (RNAi) machinery.
T cells discriminate between groups C1 and C2 HLA-C
Authors: Sim Malcolm J. W. , Stotz Zachary , Lu Jinghua , Brennan Paul , Long Eric O. , Sun Peter D.
Published: November 2021

Dimorphic residues at positions 77 and 80 delineate HLA-C allotypes into two groups, C1 and C2, which associate with disease through interactions with C1 and C2-specific natural killer cell receptors. How the C1/C2 dimorphism affects T cell recognition is unknown. Using HLA-C allotypes that differ only by the C1/C2-defining residues, we found that KRAS-G12D neoantigen specific T cell receptors (TCR) discriminated groups C1 and C2 HLA-C, due to effects on peptide presentation and TCR affinity. Structural and functional experiments combined with immunopeptidomics analysis revealed that C1-HLA-C favors smaller amino acids at the peptide C-terminus minus-1 position (pΩ-1), and that larger pΩ-1 residues diminished TCR recognition of C1-HLA-C. After controlling for peptide presentation, TCRs exhibited weaker affinities for C2-HLA-C despite conserved TCR contacts. Thus, the C1/C2 dimorphism impacts peptide presentation and HLA-C restricted T cell responses, with implications in multiple disease contexts including adoptive T cell therapy targeting KRAS-G12D-induced cancers.
An optimized ChIP-Seq framework for profiling of histone modifications in Chromochloris zofingiensis
Authors: Strenkert Daniela , Mingay Matthew , Schmollinger Stefan , Chen Cindy , O’Malley Ronan C. , Merchant Sabeeha S.
Published: November 2021

The eukaryotic green alga Chromochloris zofingiensis is a reference organism for studying carbon partitioning and a promising candidate for the production of biofuel precursors. Recent transcriptome profiling transformed our understanding of its biology and generally algal biology, but epigenetic regulation remains understudied and represents a fundamental gap in our understanding of algal gene expression. Chromatin Immunoprecipitation followed by deep sequencing (ChIP-Seq) is a powerful tool for the discovery of such mechanisms, by identifying genome-wide histone modification patterns and transcription factor-binding sites alike. Here, we established a ChIP-Seq framework for Chr. zofingiensis yielding over 20 million high quality reads per sample. The most critical steps in a ChIP experiment were optimized, including DNA shearing to obtain an average DNA fragment size of 250 bp and assessment of the recommended formaldehyde concentration for optimal DNA-protein crosslinking. We used this ChIP-Seq framework to generate a genome-wide map of the H3K4me3 distribution pattern and to integrate these data with matching RNA-Seq data. In line with observations from other organisms, H3K4me3 marks predominantly transcription start sites of genes. Our H3K4me3 ChIP-Seq data will pave the way for improved genome structural annotation in the emerging reference alga Chr. zofingiensis.
α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson’s disease
Authors: Chen Merry , Vincent Julie , Ezeanii Alexis , Wakade Saurabh , Yerigenahally Shobha , Mor Danielle E.
Published: November 2021

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the brain in a prion-like manner. While rodent models have recapitulated gut-to-brain α-synuclein transmission, animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first C. elegans models in which feeding with α-synuclein pre-formed fibrils (PFFs) induced prion-like dopamine neuron degeneration and seeding of aggregation of human α-synuclein expressed in the host. PFF acceleration of α-synuclein aggregation in C. elegans muscle cells was associated with a progressive motor deficit, whereas feeding with α-synuclein monomer produced much milder effects. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, and enzymes involved in heparan sulfate proteoglycan biosynthesis, afforded protection from PFF-induced seeding of aggregation and toxicity, as well as dopaminergic neurodegeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.
Nanopore adaptive sampling for mitogenome sequencing and bloodmeal identification in hematophagous insects
Authors: Kipp Evan J. , Lindsey Laramie L. , Blanco Cristina M. , Baker Julia , Milstein Marissa S. , Faulk Christopher , Oliver Jonathan D. , Larsen Peter A.
Published: November 2021

Blood-feeding insects are important vectors for an array of zoonotic pathogens. Despite significant research focused on well-documented insect vectors of One Health importance, resources for molecular species identification of a large number of hematophagous arthropods are limited. Advancements in next-generation sequencing technologies provide opportunities for targeting mitochondrial genomes of blood-feeding insects, as well as their bloodmeal hosts. This dual approach holds great promise for elucidating complex disease transmission pathways and enhancing the molecular resources for the identification of cryptic insect species. To this end, we leveraged the newly developed Oxford Nanopore Adaptive Sampling (NAS) pipeline to dually sequence the mitogenomes of hematophagous insects and their bloodmeals. Using NAS, we sequenced the entire mitogenomes of Aedes vexans, Culex restuans, Culex territans, and Chrysops niger and successfully identified bloodmeal hosts of Chrysops niger, Culex restuans, and Aedes trivittatus. We show that NAS has the utility to simultaneously molecularly identify blood-feeding insects and characterize disease transmission pathways through bloodmeal host identification. Moreover, our data indicate NAS can facilitate a wide array of molecular systematic studies through novel ‘phylogenetic capture’ methods. We conclude the NAS approach has great potential for informing global One Health initiatives centered on the mitigation of vector-borne disease through dual vector and bloodmeal identification.
Data-Poor Ecological Risk Assessment of Multiple Stressors
Authors: Grewelle Richard E , Mansfield Elizabeth , Micheli Fiorenza , De Leo Giulio
Published: November 2021

Ecological Risk Assessment is a formal process widely applied to terrestrial, marine, and freshwater ecosystems to evaluate the likelihood of adverse ecological effects occurring as a result of exposure to natural or anthropogenic stressors. For many species, data is sparse and semi-quantitative methodologies provide valuable insight for ecosystem management. Recent statistical developments have improved the quality of these analyses yet a rigorous theoretical framework to assess the cumulative impact of multiple stressors is lacking.

We present EcoRAMS, a web application and open-source software module that provides easy-to-use, statistically-robust ecological risk assessments of multiple stressors in data-poor contexts. The software receives attribute scores for two variables (e.g. exposure-sensitivity, productivity-susceptibility, severity-likelihood) via CSV templates and outputs results according to a probabilistic metric of risk.

We demonstrate comparative results across a range of assumptions, using simulated and empirical datasets including up to five stressors. Accounting for multiple stressors even when data is limited provides a more detailed analysis of risk that may otherwise be understated in single stressor analyses.

This application will allow quantification of risk across data-poor contexts for which statistical results have been previously unavailable. The web app format of EcoRAMS.net lowers the barrier of use for practitioners and scientists at any level of statistical training.
Malaria molecular surveillance in the Peruvian Amazon with a novel highly multiplexedPlasmodium falciparumAmpliseq assay
Authors: Kattenberg Johanna Helena , Fernandez-Miñope Carlos , van Dijk Norbert J. , Llacsahuanga Allcca Lidia , Guetens Pieter , Valdivia Hugo O. , Van geertruyden Jean-Pierre , Rovira-Vallbona Eduard , Monsieurs Pieter , Delgado-Ratto Christopher , Gamboa Dionicia , Rosanas-Urgell Anna
Published: November 2021

Molecular surveillance for malaria has great potential to support national malaria control programs (NMCPs). To bridge the gap between research and implementation, several applications (use cases) have been identified to align research, technology development, and public health efforts. For implementation at NMCPs, there is an urgent need for feasible and cost-effective tools.

We designed a new highly-multiplexed deep sequencing assay (Pf AmpliSeq), compatible with benchtop sequencers, allowing for high accuracy sequencing at higher coverage and lower cost than WGS, targeting genomic regions of interest. The novelty of the assay is in its high number of targets multiplexed in one easy workflow, combining population genetic markers with 13 near full-length resistance genes, applicable for many different use cases. We provide a first proof-of-principle forhrp2andhrp3deletion detection using amplicon sequencing. Initial sequence data processing can be performed automatically, and subsequent variant analysis requires minimal bioinformatic skills using any tabulated data analysis program.

The assay was validated with a retrospective sample collection (n = 254) from the Peruvian Amazon between 2003 and 2018. By combining phenotypic markers and a within-country 28-SNP-barcode, we were able to distinguish different lineages with multiple resistant (dhfr/dhps/crt/mdr1) haplotypes andhrp2andhrp3deletions, increasing in recent years. We found no evidence suggesting the emergence of ART-resistance in Peru. These findings indicate a parasite population under drug pressure, but susceptible to current antimalarials, and demonstrates the added value of a highly multiplexed molecular tool to inform malaria strategies and surveillance systems.

Importance

While the power of next generation sequencing technologies to inform and guide malaria control programs has become broadly recognized, integration of genomic data for operational incorporation into malaria surveillance remains a challenge in most malaria endemic countries.

The main obstacles include limited infrastructure and accessibility to high-throughput sequencing facilities and the need for local capacity to run in-country analysis of genomes at a large enough scale to be informative for surveillance. In addition, there is a lack of standardized laboratory protocols and automated analysis pipelines to generate reproducible and timely results useful for relevant stakeholders.

With our standardized laboratory and bioinformatic workflow, malaria genetic surveillance data can be readily generated by surveillance researchers and malaria control programs in endemic countries, increasing ownership and ensuring timely results for informed decision and policy-making.
Protection offered by mRNA-1273 versus BNT162b2 vaccines against SARS-CoV-2 infection and severe COVID-19 in Qatar
Authors: Abu-Raddad Laith J. , Chemaitelly Hiam , Ayoub Houssein H. , Tang Patrick , Hasan Mohammad R. , Coyle Peter , Yassine Hadi M. , Benslimane Fatiha M. , Al-Khatib Hebah A. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Butt Adeel A. , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto
Published: November 2021

BACKGROUND

Growing evidence suggests that COVID-19 vaccines differ in effectiveness against breakthrough infection or severe COVID-19, but vaccines have yet to be investigated in controlled studies that head-to-head compare immunity of one to another. This study compared protection offered by the mRNA-1273 (Moderna) vaccine with that of the BNT162b2 (Pfizer-BioNTech) vaccine in Qatar.

METHODS

In a population of 1,531,736 vaccinated persons, two matched retrospective cohort studies were designed and used to investigate differences in mRNA-1273 and BNT162b2 vaccine protection, after the first and second doses, from December 21, 2020 to October 20, 2021.

RESULTS

After dose 1, cumulative incidence of breakthrough infection was 0.79% (95% CI: 0.75-0.83%) for mRNA-1273-vaccinated individuals and 0.86% (95% CI: 0.82-0.90%) for BNT162b2-vaccinated individuals, 21 days post-injection. Adjusted hazard ratio (AHR) for breakthrough infection was 0.89 (95% CI: 0.83-0.95; p=0.001). AHR was constant in the first two weeks at 1, but it declined to 0.67 (95% CI: 0.57-0.77; p<0.001) in the third week after dose 1. AHR for any severe, critical, or fatal COVID-19 was 0.71 (95% CI: 0.53-0.95; p=0.020). After dose 2, cumulative incidence was 0.59% (95% CI: 0.55-0.64%) for mRNA-1273-vaccinated individuals and 0.84% (95% CI: 0.79-0.89%) for BNT162b2-vaccinated individuals, 180 days post-injection. AHR for breakthrough infection was 0.69 (95% CI: 0.63-0.75; p<0.001) and was largely constant over time after dose 2. AHR for any severe, critical, or fatal COVID-19 was 0.37 (95% CI: 0.10-1.41; p=0.147).

CONCLUSIONS

mRNA-1273 vaccination is associated with lower SARS-CoV-2 breakthrough infection and COVID-19 hospitalization and death than BNT162b2 vaccination, but the number of hospitalizations and deaths was exceedingly small for both vaccines. Both vaccines demonstrated strikingly similar patterns of build-up of protection after the first dose and waning of protection after the second dose.
Genomic landscape of drug response reveals novel mediators of anthelmintic resistance
Authors: Doyle Stephen R. , Laing Roz , Bartley David , Morrison Alison , Holroyd Nancy , Maitland Kirsty , Antonopoulos Alistair , Chaudhry Umer , Flis Ilona , Howell Sue , McIntyre Jennifer , Gilleard John S. , Tait Andy , Mable Barbara , Kaplan Ray , Sargison Neil , Britton Collette , Berriman Matthew , Devaney Eileen , Cotton James A.
Published: November 2021

Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to improving the efficacy and sustainability of parasite control. Here, we use a genetic cross in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies novel alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor, cky-1, in ivermectin resistance. This gene is within a locus under selection in ivermectin resistant populations worldwide; functional validation using knockout experiments supports a role for cky-1 overexpression in ivermectin resistance. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode, and identifies variants for the development of molecular diagnostics to combat drug resistance in the field.

One-Sentence Summary:

Genetic mapping of known and novel anthelmintic resistance-associated alleles in a multi-drug resistant parasitic nematode
The Xenopus Phenotype Ontology: bridging model organism phenotype data to human health and development
Authors: Fisher Malcolm E. , Segerdell Erik , Matentzoglu Nicolas , Nenni Mardi J. , Fortriede Joshua D. , Chu Stanley , Pells Troy J. , Chaturvedi Praneet , James-Zorn Christina , Sundararaj Nivitha , Lotay Vaneet S. , Ponferrada Virgilio , Wang Dong Zhuo , Kim Eugene , Agalakov Sergei , Arshinoff Bradley I. , Karimi Kamran , Vize Peter D. , Zorn Aaron M.
Published: November 2021

Background

Ontologies of precisely defined, controlled vocabularies are essential to curate the results of biological experiments such that the data are machine searchable, can be computationally analyzed, and are interoperable across the biomedical research continuum. There is also an increasing need for methods to interrelate phenotypic data easily and accurately from experiments in animal models with human development and disease.

Results

Here we present theXenopusPhenotype Ontology (XPO) to annotate phenotypic data from experiments inXenopus, one of the major vertebrate model organisms used to study gene function in development and disease. The XPO implements design patterns from the Unified Phenotype Ontology (uPheno), and the principles outlined by the Open Biological and Biomedical Ontologies (OBO Foundry) to maximize interoperability with other species and facilitate ongoing ontology management. Constructed in Web Ontology Language (OWL) the XPO combines the existing uPheno library of ontology design patterns with additional terms from theXenopusAnatomy Ontology (XAO), the Phenotype and Trait Ontology (PATO) and the Gene Ontology (GO). The integration of these different ontologies into the XPO enables rich phenotypic curation, whilst the uPheno bridging axioms allows phenotypic data fromXenopusexperiments to be related to phenotype data from other model organisms and human disease. Moreover, the simple post-composed uPheno design patterns facilitate ongoing XPO development as the generation of new terms and classes of terms can be substantially automated.

Conclusions

The XPO serves as an example of current best practices to help overcome many of the inherent challenges in harmonizing phenotype data between different species. The XPO currently consists of approximately 22,000 terms and is being used to curate phenotypes by Xenbase, theXenopusModel Organism Knowledgebase, forming a standardized corpus of genotype-phenotype data that can be directly related to other uPheno compliant resources.
Mechanistic insights into the enhancement or inhibition of phase separation by polyubiquitin chains of different lengths or linkages
Authors: Dao Thuy P. , Yang Yiran , Presti Maria F. , Cosgrove Michael S. , Hopkins Jesse B. , Ma Weikang , Loh Stewart N. , Castañeda Carlos A.
Published: November 2021

Ubiquitin-binding shuttle UBQLN2 mediates crosstalk between proteasomal degradation and autophagy, likely via interactions with K48- and K63-linked polyubiquitin chains, respectively. UBQLN2 is recruited to stress granules in cells and undergoes liquid-liquid phase separation (LLPS)in vitro. However, interactions with ubiquitin or multivalent K48-linked chains eliminate LLPS. Here, we found that, although some polyubiquitin chain types (K11-Ub4 and K48-Ub4) did generally inhibit UBQLN2 LLPS, others (K63-Ub4, M1-Ub4 and a designed tetrameric ubiquitin construct) significantly enhanced LLPS. Using nuclear magnetic resonance (NMR) spectroscopy and complementary biophysical techniques, we demonstrated that these opposing effects stem from differences in chain conformations, but not in affinities between chains and UBQLN2. Chains with extended conformations and increased accessibility to the ubiquitin binding surface significantly promoted UBQLN2 LLPS by enabling a switch between homotypically to partially heterotypically-driven phase separation. Our study provides mechanistic insights into how the structural and conformational properties of polyubiquitin chains contribute to heterotypic phase separation with ubiquitin-binding shuttles and adaptors.

Highlights

Ubiquitin or short polyubiquitin chains bind to phase separation-driving stickers on UBQLN2 and inhibit its phase separation whereas longer chains provide the multivalency needed to enhance UBQLN2 phase separation.

Phase separation of UBQLN2 is promoted over a wide range of Ub:UBQLN2 ratios in the presence of extended M1- and K63-linked Ub4 chains, but not compact K11- and K48-linked Ub4 chains.

Chain conformation and accessibility of the Ub interacting surface is a driving factor of UBQLN2/polyUb co-phase separation.

UBQLN2 condensates assemble duringin vitroenzymatic assembly of K63-linked polyUb chains as free ubiquitin is reduced.
A de novo matrix for macroscopic living materials from bacteria
Authors: Molinari Sara , Tesoriero Robert F. , Li Dong , Sridhar Swetha , Cai Rong , Soman Jayashree , Ryan Kathleen R. , Ashby Paul D. , Ajo-Franklin Caroline M.
Published: November 2021

Summary Paragraph

Engineered living materials (ELMs) are composites of living cells embedded in a biopolymer matrix that combine the desirable properties of natural biomaterials with non-natural, tailored properties. ELMs with a wide range of sophisticated biological functions have been created by engineering the embedded cells using synthetic biology. Engineering a de novo biomolecular matrix would offer control over material assembly, structure, and composition, thus enabling us to grow macroscopic ELMs with customizable mechanical properties. However, we have lacked the genetic tools and design rules to genetically encode a synthetic matrix that programs collective cell self-organization into macroscopic structures. Here we report growth of macroscopic ELMs from Caulobacter crescentus cells that display and secrete an engineered self-interacting protein. This protein formed an extracellular de novo matrix and assembled cells into hierarchically-ordered, centimeter-scale ELMs. We showed that the mechanical, catalytic, and morphological properties of these ELMs can be tuned through genetic modification of the matrix. Our work identifies novel genetic tools, design and assembly rules for growing macroscopic ELMs with both wide-ranging mechanical properties and customizable functions. We anticipate the modularity of this approach will permit the incorporation of different protein polymers in the de novo matrix, thus allowing to generate ELMs with a variety of desired structures and compositions of the bulk material. We envision specific matrix properties that can be combined synergistically with existing cellular functions to greatly expand the opportunities for ELMs in human health, energy, and the environment.
Recurrent neural circuits overcome partial inactivation by compensation and re-learning
Authors: Bredenberg Colin , Savin Cristina , Kiani Roozbeh
Published: November 2021

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Technical advances in artificial manipulation of neural activity have precipitated a surge in studying the causal contribution of brain circuits to cognition and behavior. However, complexities of neural circuits challenge interpretation of experimental results, necessitating theoretical frameworks for system-atic explorations. Here, we take a step in this direction, using, as a testbed, recurrent neural networks trained to perform a perceptual decision. We show that understanding the computations implemented by network dynamics enables predicting the magnitude of perturbation effects based on changes in the network’s phase plane. Inactivation effects are weaker for distributed network architectures, are more easily discovered with non-discrete behavioral readouts (e.g., reaction times), and vary considerably across multiple tasks implemented by the same circuit. Finally, networks that can “learn” during inactivation recover function quickly, often much faster than the original training time. Our framework explains past empirical observations by clarifying how complex circuits compensate and adapt to perturbations.
Transcriptomic plasticity and symbiont shuffling underpin Pocillopora acclimatization across heat-stress regimes in the Pacific Ocean
Authors: Armstrong Eric J , Lê-Hoang Julie , Carradec Quentin , Aury Jean-Marc , Noel Benjamin , Poulain Julie , Belser Caroline , Da Silva Corinne , Wincker Patrick ,   Tara Pacific Consortium
Published: November 2021

The characterization of adaptation and acclimation capacities of coral holobionts is crucial for anticipating the impact of global climate change on coral reefs. Understanding the extent to which the coral host and its photosymbionts contribute to adaptive and/or plastic responses in the coral metaorganism is important. In this study, we highlight new and complex links between coral genomes, transcriptomes, and environmental features in Pocilloporid corals at basin-wide scale. We analyzed metagenomic and metatranscriptomic sequence data from Pocillopora colonies sampled from 11 islands across the Pacific Ocean in order to investigate patterns of gene expression in both the host and photosymbiont across an environmental gradient. Single nucleotide polymorphisms (SNPs) analysis partitioned coral hosts and algal photosymbionts into five genetic lineages each. We observed strong host-symbiont fidelity across environments except at islands where recent and/or historical heat stress may have induced a symbiont shift towards more heat-tolerant lineages in some colonies. Host gene expression profiles were strongly segregated by genetic lineage and environment, and were significantly correlated with several historical sea surface temperature (SST) traits. Symbiont expression profiles were less dependent on environmental context than the host and were primarily driven by algal genotype. Overall, our results suggest a three-tiered strategy underpinning thermal acclimatization in Pocillopora holobionts with 1) host-photosymbiont fidelity, 2) host transcriptomic plasticity, and 3) photosymbiont shuffling playing progressive roles in response to elevated SSTs. Our data provide a reference for the biological state of coral holobionts across the Indo-Pacific and demonstrate the power of disentangling environmental and genetic effects to provide new insights into corals’ capacities for acclimatization and adaptation under environmental change.
Neurotransmission and neuromodulation systems in the learning and memory network ofOctopus vulgaris
Authors: Stern-Mentch Naama , Winter Gabriela , Belenky Michael , Moroz Leonid , Hochner Binyamin
Published: November 2021

The vertical lobe (VL) in the octopus brain plays an essential role in its sophisticated learning and memory. Early anatomical studies suggested that the VL is organized in a “fan-out fan-in” connectivity matrix comprising only three morphologically identified neuron types; input axons from the superior frontal lobe (SFL) innervatingen passantmillions of small amacrine interneurons (AMs) which converge sharply onto large VL output neurons (LNs). Recent physiological studies confirmed the feedforward excitatory connectivity: a glutamatergic synapse at the first SFL-to-AM synaptic layer and a cholinergic AM-to-LNs synapse. SFL-to-AMs synapses show a robust hippocampal-like activity-dependent long-term potentiation (LTP) of transmitter release. 5-HT, octopamine, dopamine and nitric oxide modulate short- and long-term VL synaptic plasticity. Here we present a comprehensive histolabeling study to better characterize the neural elements in the VL. We generally confirmed glutamatergic SFLs and cholinergic AMs. Intense labeling for NOS activity in the AMs neurites fitted with the NO-dependent presynaptic LTP mechanism at the SFL-to-AM synapse. New discoveries here reveal more heterogeneity of the VL neurons than previously thought. GABAergic AMs suggest a subpopulation of inhibitory interneurons in the first input layer. Clear GABA labeling in the cell bodies of LNs supported an inhibitory VL output yet the LNs co-expressed FMRFamide-like neuropeptides suggesting an additional neuromodulatory role of the VL output. Furthermore, a group of LNs was glutamatergic. A new cluster of cells organized in a “deep nucleus” showed rich catecholaminergic labeling and may play a role in intrinsic neuromodulation.In situhybridization and immunolabeling allowed characterization and localization of a rich array of neuropeptides and neuromodulatores, likely involved in reward/punishment signals. This analysis of the fast transmission system, together with the newly found cellular elements helps integrate behavioral, physiological, pharmacological and connectome findings into a more comprehensive understanding of an efficient learning and memory network.
A semantics, energy-based approach to automate biomodel composition
Authors: Shahidi Niloofar , Pan Michael , Tran Kenneth , Crampin Edmund J. , Nickerson David P.
Published: November 2021

Hierarchical modelling is essential to achieving complex, large-scale models. However, not all modelling schemes support hierarchical composition, and correctly mapping points of connection between models requires comprehensive knowledge of each model’s components and assumptions. To address these challenges in integrating biosimulation models, we propose an approach to automatically and confidently compose biosimulation models. The approach uses bond graphs to combine aspects of physical and thermodynamics-based modelling with biological semantics. We improved on existing approaches by using semantic annotations to automate the recognition of common components. The approach is illustrated by coupling a model of the Ras-MAPK cascade to a model of the upstream activation of EGFR. Through this methodology, we aim to assist researchers and modellers in readily having access to more comprehensive biological systems models.

Author summary

Detailed, multi-scale computational models bridging from biomolecular processes to entire organs and bodies have the potential to revolutionise medicine by enabling personalised treatments. One of the key challenges to achieving these models is connecting together the vast number of isolated biosimulation models into a coherent whole. Using recent advances in both modelling techniques and biological standards in the scientific community, we developed an approach to integrate and compose models in a physics-based environment. This provides significant advantages, including the automation of model composition and post-model-composition adjustments. We anticipate that our approach will enable the faster development of realistic and accurate models to understand complex biological systems.
Wnt5A Signaling Blocks Progression of Experimental Visceral Leishmaniasis
Authors: Maity Shreyasi , Chakraborty Arijit , Mahata Sushil , Roy Syamal , Das Anjan Kumar , Sen Malini
Published: November 2021

Visceral Leishmaniasis, caused by L. donovani infection is fatal if left untreated. The intrinsic complexity of visceral leishmaniasis complicated further by the increasing emergence of drug resistant L. donovani strains warrants fresh investigations into host defense schemes that counter infections. Accordingly, using a mouse model of experimental visceral leishmaniasis we explored the utility of host Wnt5A in restraining L. donovani infection, using both antimony sensitive and antimony resistant L. donovani strains. We found that Wnt5A heterozygous (Wnt5A +/-) mice are more susceptible to L. donovani infection than their wild type (Wnt5A +/+) counterparts as depicted by the respective Leishman Donovan Units (LDU) enumerated from the liver and spleen harvested from infected mice. Higher LDU in Wnt5A +/-mice correlated with increased level of plasma gammaglobulin, liver granuloma and disorganization of splenic germinal centers. Progression of infection in mice by both antimony sensitive and antimony resistant strains of L. donovani could be prevented by activation of Wnt5A signaling as evident from the lowered LDU and gammaglobulin level, and intactness of splenic germinal centers through intravenous administration of rWnt5A prior to L. donovani infection. Wnt5A mediated blockade of L. donovani infection correlated with the preservation of splenic macrophages and activated T cells, and a TH1 like cytokine thrust. Taken together our results indicate that depletion of Wnt5A promotes susceptibility to visceral leishmaniasis and revamping Wnt5A signaling in the host is able to curb L. donovani infection irrespective of antimony sensitivity or resistance and mitigate the progression of visceral leishmaniasis.