bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Antimalarial Compounds that Inhibit Apicomplexan AP2 Proteins in the Human Malaria Parasite Plasmodium falciparum
Authors: Russell Timothy , De Silva Erandi K. , Crowley Valerie , Shaw-Saliba Kathryn , Dube Namita , Josling Gabrielle , Pasaje Charisse Flerida A. , Kouskoumvekaki Irene , Panagiotou Gianni , Niles Jacquin C. , Jacobs-Lorena Marcelo , Okafor C. Denise , Gamo Francisco-Javier , Llinás Manuel 
Published: April 2022

AbstractPlasmodium parasites are reliant on the Apicomplexan AP2 (ApiAP2) transcription factor family to regulate gene expression programs. AP2 DNA binding domains have no homologs in the human or mosquito host genomes, making them potential antimalarial drug targets. Using an in-silico screen to dock thousands of small molecules into the crystal structure of the AP2-EXP (Pf3D7_1466400) AP2 domain (PDB:3IGM), we identified compounds that interact with this domain. Four compounds were found to compete for DNA binding with AP2-EXP and at least one additional ApiAP2 protein. Our top ApiAP2 competitor compound perturbs the transcriptome of P. falciparum trophozoites and results in a decrease in abundance of log2 fold change > 2 for 50% (46/93) of AP2-EXP target genes. Additionally, two ApiAP2 competitor compounds have multi-stage anti-Plasmodium activity against blood and mosquito stage parasites. In summary, we describe a novel set of antimalarial compounds that are targeted against the ApiAP2 family of proteins. These compounds may be used for future chemical genetic interrogation of ApiAP2 proteins or serve as starting points for a new class of antimalarial therapeutics.Author SummaryPlasmodium parasites are the causative agent of malaria, which resulted in over 600,000 deaths in 2021. Due to resistance arising for every antimalarial therapeutic deployed to date, new drug targets and druggable pathways must be explored. To address this concern, we used a molecular docking screen to predict competitors of DNA binding by the parasite specific family of Apicomplexan AP2 (ApiAP2) transcription factor proteins for testing in vitro and in vivo. We find that ApiAP2 competing compounds have antimalarial activity consistent with the disruption of gene regulation. This work will further our understanding of both the biological role and targetability of parasite transcriptional regulation.
Reactive Oxygen Species Signaling Differentially Controls Wound Healing and Regeneration
Authors: Van Huizen Alanna V. , Hack Samantha J. , Greene Jacqueline M. , Kinsey Luke J. , Beane Wendy S. 
Published: April 2022

AbstractReactive oxygen species (ROS), such as hydrogen peroxide, are conserved and critical components of both wound healing and regeneration. Even though millions are affected each year by poor wound healing and an inability to restore functional tissue, how the same ROS-mediated signaling regulates these two different processes is not fully understood. Here, we investigate the role(s) of ROS during planarian wound healing and regeneration. We show ROS accumulate after injury and are required for wound closure (by promoting cytoskeletal movements) and regrowth (by promoting blastema formation). We found that different threshold levels of ROS regulate separate downstream targets to control wound healing (jun-1) versus regeneration (hsp70). By only manipulating ROS levels, we were able to control which injury-induced program was initiated: failure to close (chronic wound), healing only (no blastema), or full regeneration. Our results demonstrate that healing versus regenerative outcomes are based on differential ROS-mediated gene expression soon after injury. This study highlights ROS signaling as a potential therapeutic means to control wound repair mechanisms in multiple contexts. Therefore, investigating the mechanisms by which ROS control different tissue repair processes will be necessary not only for regenerative medicine but to improve clinical outcomes for chronic wounds and fibrosis.
Single-molecule tracking of Nodal and Lefty in live zebrafish embryos supports hindered diffusion model
Authors: Kuhn Timo , Landge Amit N. , Mörsdorf David , Coßmann Jonas , Gerstenecker Johanna , Müller Patrick , Gebhardt J. Christof M. 
Published: April 2022

AbstractThe influential hindered diffusion model postulates that the global movement of a signaling molecule through an embryo is affected by local tissue geometry and binding-mediated hindrance, but these effects have not been directly demonstratedin vivofor any signaling molecule. Nodal and Lefty are a prime example of an activator-inhibitor signaling pair whose different global diffusivities are thought to arise from differential hindrance. Here, we used single-molecule tracking of Nodal and Lefty to directly probe the tenets of the hindered diffusion model on the nanoscale. We visualized individual fluorescently-tagged Nodal and Lefty molecules in developing zebrafish embryos using reflected light-sheet microscopy. Single-particle tracking revealed molecules in three states: molecules diffusing in extracellular cavities, molecules diffusing within cell-cell interfaces, and molecules bound to cell membranes. While the diffusion coefficients of molecules were high in extracellular cavities, mobility was reduced and bound fractions were higher within cell-cell interfaces; counterintuitively, molecules nevertheless accumulated in cavities. Using agent-based simulations, we identified the geometry of the extracellular space as a key factor influencing the accumulation of molecules in cavities. For Nodal, the fraction of molecules in the bound state was larger than for Lefty, and individual Nodal molecules had binding times of tens of seconds. Together, our single-molecule measurements and simulations provide direct support for the hindered diffusion model in a developing embryo and yield unprecedented insights into the nanometer to micrometer scale transport mechanisms that together lead to macroscopic signal dispersal and gradient formation.
Architecture of the chikungunya virus replication organelle
Authors: Laurent Timothée , Kumar Pravin , Liese Susanne , Zare Farnaz , Jonasson Mattias , Carlson Andreas , Carlson Lars-Anders 
Published: April 2022

AbstractAlphaviruses are mosquito-borne viruses that cause serious disease in humans and other mammals. Along with its mosquito vector, the alphavirus chikungunya virus (CHIKV) has spread explosively in the last 20 years, and there is no approved treatment for chikungunya fever. On the plasma membrane of the infected cell, CHIKV generates dedicated organelles for viral RNA replication, so-called spherules. Whereas structures exist for several viral proteins that make up the spherule, the architecture of the full organelle is unknown. Here, we use cryo-electron tomography to image CHIKV spherules in their cellular context. This reveals that the viral protein nsP1 serves as a base for the assembly of a larger protein complex at the neck of the membrane bud. Biochemical assays show that the viral helicase-protease nsP2, while having no membrane affinity on its own, is recruited to membranes by nsP1. The tomograms further reveal that full-sized spherules contain a single copy of the viral genome in double-stranded form. Finally, we present a mathematical model that explains the membrane remodeling of the spherule in terms of the pressure exerted on the membrane by the polymerizing RNA, which provides a good agreement with the experimental data. The energy released by RNA polymerization is found to be sufficient to remodel the membrane to the characteristic spherule shape.
Pan-genome evolution and its association with divergence of metabolic functions in Bifidobacterium genus
Authors: Deb Sushanta 
Published: April 2022

AbstractMany works have been performed to characterize the genomic evolution and diversity among type species of the Bifidobacterium genus due to its health-promoting effect on their host. However, those studies were mainly based on species-level taxonomic resolution, adaptation, and characterization of carbohydrate metabolic features of the bifidobacterial species. Here, a comprehensive analysis of the type strain genome unveils the association of pan-genome evolution with the divergence of metabolic function of the Bifidobacterium genus. This study also has demonstrated that the horizontal gene transfer and genome expansion and reduction events in the evolutionary history influencing the diversity of metabolic functions of bifidobacterium genus. Furthermore, the genome-based search of probiotic traits among all the available bifidobacterial type strains gives hints on type species, that could confer health benefits to nutrient-deficient individuals. Altogether, the present study provides insight into the developments of genomic evolution, functional divergence, and potential probiotic type species of the Bifidobacterium genus.
Impact of temperature and time on DNA-free Cas9-ribonucleoprotein mediated gene editing in wheat protoplasts and immature embryos
Authors: Poddar Snigdha , Tanaka Jaclyn , Running Katherine L.D. , Kariyawasam Gayan K. , Faris Justin D. , Friesen Timothy L. , Cho Myeong-Je , Cate Jamie H. D. , Staskawicz Brian 
Published: April 2022

SummaryThe advancement of precision engineering for crop trait improvement is important in the face of rapid population growth, climate change, and disease. To this end, targeted double-stranded break technology using RNA-guided Cas9 has been adopted widely for genome editing in plants. Agrobacterium or particle bombardment-based delivery of plasmids encoding Cas9 and guide RNA (gRNA) is common, but requires optimization of expression and often results in random integration of plasmid DNA into the plant genome. Recent advances have described gene editing by the delivery of Cas9 and gRNA as pre-assembled ribonucleoproteins (RNPs) into various plant tissues, but with moderate efficiency in resulting regenerated plants. In this report we describe significant improvements to Cas9-RNP mediated gene editing in wheat. We demonstrate that Cas9-RNP assays in protoplasts are a fast and effective tool for rational selection of optimal gRNAs for gene editing in regenerable immature embryos (IEs), and that high temperature treatment enhances gene editing rates in both tissue types. We also show that Cas9-mediated editing persists for at least 14 days in gold particle bombarded wheat IEs. The regenerated edited wheat plants in this work are recovered at high rates in the absence of exogenous DNA and selection. With this method, we produce knockouts of a set of three homoeologous genes and two pathogenic effector susceptibility genes that result in insensitivity to corresponding necrotrophic effectors produced by Parastagonospora nodorum. The establishment of highly efficient, DNA-free gene editing technology holds promise for accelerated trait diversity production in an expansive array of crops.
Serious underlying medical conditions and COVID-19 vaccine hesitancy
Authors: Day Daphne , Grech Lisa , Nguyen Mike , Bain Nathan , Kwok Alastair , Harris Sam , Chau Hieu , Chan Bryan , Blennerhassett Richard , Nott Louise , Hamad Nada , Tognela Annette , Hoffman David , McCartney Amelia , Webber Kate , Wong Jennifer , Underhill Craig , Sillars Brett , Winkel Antony , Savage Mark , Loe Bao Sheng , Freeman Daniel , Segelov Eva 
Published: April 2022

AbstractObjectiveTo examine vaccine uptake, hesitancy and explanatory factors amongst people with serious and/or chronic health conditions, including the impact of underlying disease on attitudes to vaccination.DesignCross-sectional survey.SettingTen Australian health services.Participants4683 patients (3560 cancer, 842 diabetes and 281 multiple sclerosis) receiving care at the health services participated in the 42-item survey, between June 30 to October 5, 2021.Main outcome measuresSociodemographic and disease-related characteristics, COVID-19 vaccine uptake, and the scores of three validated scales which measured vaccine hesitancy and vaccine-related beliefs generally and specific to the participants’ disease, including the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale. Multivariable logistic regression was used to determine the associations between scale scores and vaccine uptake.ResultsOf all participants, 81.5% reported having at least one COVID-19 vaccine. Unvaccinated status was associated with younger age, female sex, lower education and income, English as a second language, and residence in regional areas (all p<0.05). Unvaccinated participants were more likely to report greater vaccine hesitancy and more negative perceptions toward vaccines (all p<0.05). Disease-related vaccine concerns were associated with unvaccinated status and hesitancy, including greater complacency about COVID-19 infection, and concerns relating to vaccine efficacy and impact on their disease and/or treatment (all p<0.05).ConclusionsDisease-specific concerns impact COVID-19 vaccine-related behaviours and beliefs in people with serious and/or chronic health conditions. This highlights the need to develop targeted strategies and education about COVID-19 vaccination to support medically vulnerable populations and health professionals.Trial registrationACTRN12621001467820
Prophylactic and reactive vaccination strategies for healthcare workers against MERS-CoV
Authors: Laydon Daniel J , Cauchemez Simon , Hinsley Wes R , Bhatt Samir , Ferguson Neil M 
Published: April 2022

AbstractSeveral vaccines candidates are in development against Middle East respiratory syndrome–related coronavirus (MERS-CoV), which remains a major public health concern. Using individual-level data on the 2013-2014 Kingdom of Saudi Arabia epidemic, we employ counterfactual analysis on inferred transmission trees (“who-infected-whom”) to assess potential vaccine impact. We investigate the conditions under which prophylactic “proactive” campaigns would outperform “reactive” campaigns (i.e. vaccinating either before or in response to the next outbreak), focussing on healthcare workers. Spatial scale is crucial: if vaccinating healthcare workers in response to outbreaks at their hospital only, proactive campaigns perform better, unless efficacy has waned significantly. However, campaigns that react at regional or national level consistently outperform proactive campaigns. Measures targeting the animal reservoir reduce transmission linearly, albeit with wide uncertainty. Substantial reduction of MERS-CoV morbidity and mortality is possible when vaccinating healthcare workers, underlining the need for at-risk countries to stockpile vaccines when available.
A critical developmental interval of coupling axon branching to synaptic degradation during neural circuit formation
Authors: Dutta Suchetana B. , Linneweber Gerit Arne , Andriatsilavo Maheva , Hiesinger Peter Robin , Hassan Bassem A 
Published: April 2022

ABSTRACTThe emergence of neuronal wiring specificity requires stabilization of dynamic axonal branches at sites of selective synapse formation. Models that explain how axonal branching is coupled to synaptogenesis postulate molecular regulators acting in a spatiotemporally restricted fashion. We report that Epidermal Growth Factor Receptor (EGFR) activity is required in presynaptic axonal branches during two distinct temporal intervals to regulate circuit wiring in the developing Drosophila visual system. EGFR is required early to regulate primary axonal branching and independently again later to prevent autophagic degradation of the synaptic active zone protein Bruchpilot (Brp). The protection of synaptic material during this later interval of wiring ensures the stabilization of terminal branches, circuit connectivity and appropriate visual behavior. Phenotypes of EGFR inactivation were rescued by increasing Brp levels or downregulating autophagic genes. We identify a temporally restricted molecular mechanism required for coupling axonal branching and synaptic stabilization that contributes to the emergence of neuronal wiring specificity.
Structural studies of hepatitis C virus non-structural protein-5b of genotype 4a
Authors: Gaber Hanaa , Niessing Dierk , Protzer Ulrike , Janowski Robert 
Published: April 2022

AbstractHepatitis C virus genotype 4a non-structural protein-5b is an RNA-dependent RNA-polymerase responsible for the efficient virus genome replication. It has been of great interest as a drug target. The availability of the crystal structure of HCV genotype 4a NS5b would facilitate the structure-based drug design. Here we report the X-ray structure of NS5b solved at 3.1 Å resolution, setting the groundwork for the above-described therapeutic strategy.SynopsisX-ray structure of hepatitis C virus genotype 4a non-structural protein-5b, RNA-dependent RNA-polymerase responsible for the efficient virus genome replication.
Culexarchaeia, a novel archaeal class of anaerobic generalists inhabiting geothermal environments
Authors: Kohtz Anthony J. , Jay Zackary J. , Lynes Mackenzie , Krukenberg Viola , Hatzenpichler Roland 
Published: April 2022

AbstractGeothermal environments, including terrestrial hot springs and deep-sea hydrothermal sediments, often contain many poorly understood lineages of archaea. Here, we recovered ten metagenome-assembled genomes (MAGs) from geothermal sediments and propose that they constitute a new archaeal class within the TACK superphylum, “Candidatus Culexarchaeia”, named after the Culex Basin in Yellowstone National Park. Culexarchaeia harbor distinct sets of proteins involved in key cellular processes that are either phylogenetically divergent or are absent from other closely related TACK lineages, with a particular divergence in cell division and cytoskeletal proteins. Metabolic reconstruction revealed that Culexarchaeia have the capacity to metabolize a wide variety of organic and inorganic substrates. Notably, Culexarchaeia encode a unique modular, membrane associated, and energy conserving [NiFe]-hydrogenase complex that potentially interacts with heterodisulfide reductase (Hdr) subunits. Comparison of this [NiFe]-hydrogenase complex with similar complexes from other archaea suggests that interactions between membrane associated [NiFe]-hydrogenases and Hdr may be more widespread than previously appreciated in both methanogenic and non-methanogenic lifestyles. The analysis of Culexarchaeia further expands our understanding of the phylogenetic and functional diversity of lineages within the TACK superphylum and the ecology, physiology, and evolution of these organisms in extreme environments.
Conduction velocity along a key white matter tract is associated with autobiographical memory recall ability
Authors: Clark Ian A. , Mohammadi Siawoosh , Callaghan Martina F. , Maguire Eleanor A. 
Published: April 2022

AbstractConduction velocity is the speed at which electrical signals travel along axons and is a crucial determinant of neural communication. Inferences about conduction velocity can now be made in vivo in humans using a measure called the magnetic resonance (MR) g-ratio. This is the ratio of the inner axon diameter relative to that of the axon plus the myelin sheath that encases it. Here, in the first application to cognition, we found that variations in MR g-ratio, and by inference conduction velocity, of the parahippocampal cingulum bundle were associated with autobiographical memory recall ability in 217 healthy adults. This tract connects the hippocampus with a range of other brain areas. We further observed that the association seemed to be with inner axon diameter rather than myelin content. The extent to which neurites were coherently organised within the parahippocampal cingulum bundle was also linked with autobiographical memory recall ability. Moreover, these findings were specific to autobiographical memory recall, and were not apparent for laboratory-based memory tests. Our results offer a new perspective on individual differences in autobiographical memory recall ability, highlighting the possible influence of specific features of white matter microstructure when recalling detailed memories of our real-life past experiences.
Phylogenetic and Ecological Trends in Specialization: Disentangling the Drivers of Ectoparasite Host Specificity
Authors: Brown Alexis M. , Speer Kelly A. , Teixeira Tiago , Clare Elizabeth , Simmons Nancy B. , Balbuena Juan A. , Dick Carl W. , Dittmar Katharina , Perkins Susan 
Published: April 2022

AbstractEcological specialization reflects both evolutionary and ecological processes. For parasitic taxa, ecological specialization can be assessed as the degree to which a parasite species will associate with certain host species, a property known as host specificity.Ectoparasitic bat flies have been previously reported as highly host specific, presumably due to a history of coevolution with their bat hosts. However, there is conflicting evidence of coevolution between bats and bat flies. Resource-driven competition between parasite individuals and between species may also be important in explaining patterns of bat fly specificity.To test the importance of evolutionary and ecological factors on bat fly specificity, we collected and identified 21 bat fly species from 16 host bat species from the State of Rio de Janeiro in Brazil. We generated a bat fly species phylogeny from molecular data, estimatedd’specialization values (a metric of specificity), and used linear and cophylogenetic models to compare the importance of various drivers of parasite ecological specialization.We found that bat fly co-occurrence frequency (a proxy for interspecific competition) and mean infection intensity (a proxy for intraspecific competition) best predicted patterns of bat fly specialization. Co-occurrence frequency had a significantly negative association with specialization, while mean infection intensity has a significantly positive association with specialization. Coevolutionary congruence had a small effect size and did not significantly predict parasite specialization.We found multiple shifts toward more generalized host niches across the bat fly phylogeny. Our results suggest that ecological processes such as resource-driven competition may be more important than evolutionary processes in shaping bat fly host specialization networks.Bat flies showed variable degrees of host specialization, parasitized phylogenetically distant host species, and showed low phylogenetic congruence to their hosts. This suggests that as a group, bat flies may show flexibility in their host preference phenotypes and may change their host associations in the face of environmental disturbance.