bluuebunny/crossref_metadata_2025_split huggingface dataset:
Battle for the histones: a secreted bacterial sirtuin from Campylobacter jejuni activates neutrophils and induces inflammation during infection
Authors: Callahan Sean M. , Hancock Trevor J. , Doster Ryan S. , Parker Caroline B. , Wakim Mary E. , Gaddy Jennifer A. , Johnson Jeremiah G. 
Published: July 2022

AbstractHistone modifications alter numerous cornerstone processes in eukaryotes, including metabolism, physiology, and immunity. Numerous bacterial pathogens can alter expression of host-derived sirtuins to deacetylate histones in order to promote infection, yet, a bacterial-derived sirtuin has yet to be investigated to deacetylate host histones. Using Campylobacter jejuni, the leading cause of bacterial-derived gastroenteritis, we found a secreted sirtuin, SliP, which binds to and deacetylates neutrophil histones. We found neutrophil activation and extrusion of neutrophil extracellular traps was SliP dependent, whereby sliP mutants are unable to activate neutrophils or promote NETosis. Leveraging the mouse model of campylobacteriosis, we further demonstrate the sliP mutant can efficiently infect IL-10-/- mice, but induction of proinflammatory cytokine production and gastrointestinal pathology is SliP-dependent. In conclusion, we investigate a unique bacterial effector which targets host histones and is responsible for the inflammatory response and tissue pathology observed during campylobacteriosis.HighlightsC. jejuni encodes a secreted effector, SliP, which functions as a canonical sirtuinSliP binds to and deacetylates neutrophil histone H3 during bacterial infectionC. jejuni-induced neutrophil activation and NETosis are SliP-dependentInflammation and tissue pathology during C. jejuni infection is SliP-dependent
Antigen binding kinetics are quite different for B-cell receptors and free antibodies
Authors: García-Sánchez Miguel , Castro Mario , Faro José 
Published: July 2022

Since the pioneering works of Berg and Purcell, discriminating between diffusion followed by binding has played a central role in understanding cell signaling. B-cell receptors (BCR) and antibodies (Ab) challenge that simplified view as binding to antigen follows after a chain of diffusion and rotations, including whole molecule rotation, and independent tilts and twists of their Fab arms due to their Y-shaped structure and flexibility. In this paper, we combine analytical calculations with Brownian simulations to derive the first-passage times due to these three rotations positioning the Fab paratopes at a proper distance and orientation required for antigen binding. Applying these estimations and those for 2-dimensional (2D) and 3D translational diffusion of, respectively, BCRs and Abs, we evidence that measuring Ab-Ag effective kinetic binding rates using experimental methods in which the analyte is in solution gives values proportional to the intrinsic binding rates,k+andk−, only for values ofk+up to 109s−1, beyond which a plateau of the effective 3D on rate between 108M−1s−1and 109M−1s−1is attained. Moreover, for BCR-Ag interactions, the effective 2D on and off binding rates can be inferred from the corresponding effective 3D on and off rates only for values of effective 3D on rates lower than 106M−1s−1. This is highly relevant when one seeks to relate BCR-antigen binding strength and B cell response, particularly during germinal center reactions. Thus, there is an urgent need to revisit our current understanding of the BCR-antigen kinetic rates in germinal centers using state-of-the-art experimental assays for BCR-Ag interactions.Significance StatementIn germinal centers, binding between BCRs and antigen (Ag) tethered on the membrane of follicular dendritic cells occurs via two-dimensional (2D) membrane-to-membrane interactions. In contrast, inin vitroassays antibody (Ab)-antigen interactions occur with one component in solution. Structurally, there are large qualitative and quantitative differences between BCR-Ag 2D and Ab-Ag 3D translational and rotational diffusion processes, with the 2D translational diffusion being about 1000-fold lower than the 3D one. Moreover, the effective binding kinetics of both BCR-Ag and Ab-Ag interactions strongly deviate from the intrinsic molecular on and off rates. Here we expose this mismatch and, performing numerical and analytical calculations, quantify the ranges for which the experimental in-vitro data is informative on the BCR-Ag binding strength.
Tecovirimat is highly efficient on the Monkeypox virus lineage responsible for the international 2022 outbreak
Authors: Frenois-Veyrat Gaëlle , Gallardo Franck , Gorgé Olivier , Marcheteau Elie , Ferraris Olivier , Baidaliuk Artem , Favier Anne-Laure , Enfroy Cécile , Holy Xavier , Lourenco Jérémy , Khoury Rhéa , Nolent Flora , Grosenbach Douglas W. , Hruby Dennis , Ferrier Audrey , Iseni Frédéric , Simon-Loriere Etienne , Tournier Jean-Nicolas 
Published: July 2022

AbstractThe ongoing monkeypox virus (MPXV) outbreak is the largest ever recorded outside of Africa. Genomic analysis revealed a divergent phylogenetic lineage within clade 3, and atypical clinical presentations have been noted. We report the sequencing and isolation of the virus from the first clinical case diagnosed in France in May 2022. We tested thein vitroeffect of tecovirimat (ST-246), a FDA approved drug, against this novel strain, showing efficacy at the nanomolar range. In comparison, cidofovir showed activity at micromolar concentrations. These results and the safety profile of tecovirimat strongly support its use in clinical care of severe forms for the 2022 MPXV outbreak.
Deep generative modeling and clustering of single cell Hi-C data
Authors: Liu Qiao , Zeng Wanwen , Zhang Wei , Wang Sicheng , Chen Hongyang , Jiang Rui , Zhou Mu , Zhang Shaoting 
Published: July 2022

AbstractDeciphering 3D genome conformation is important for understanding gene regulation and cellular function at a spatial level. The recent advances of single cell Hi-C technologies have enabled the profiling of the 3D architecture of DNA within individual cell, which allows us to study the cell-to-cell variability of 3D chromatin organization. Computational approaches are in urgent need to comprehensively analyze the sparse and heterogeneous single cell Hi-C data. Here, we proposed scDEC-Hi-C, a new framework for single cell Hi-C analysis with deep generative neural networks. scDEC-Hi-C outperforms existing methods in terms of single cell Hi-C data clustering and imputation. Moreover, the generative power of scDEC-Hi-C could help unveil the heterogeneity of chromatin architecture across different cell types. We expect that scDEC-Hi-C could shed light on deepening our understanding of the complex mechanism underlying the formation of chromatin contacts. scDEC-Hi-C is freely available at https://github.com/kimmo1019/scDEC-Hi-C.Key pointsscDEC-Hi-C provides an end-to-end framework based on autoencoder and deep generative model to comprehensively analyze single cell Hi-C data, including low-dimensional embedding and clustering.Through a series of experiments including single cell Hi-C data clustering and structural difference identification, scDEC-Hi-C demonstrates suprioir performance over existing methods.In the downstream analysis of chromatin loops from single cell Hi-C data, scDEC-Hi-C is capable of significantly enhancing the ability for identifying single cell chromatin loops by data imputation.
Intergenerational effects from spatial and genetic environment predict early-life social network structure
Authors: Franks Victoria R. , Thorogood Rose , Brekke Patricia 
Published: July 2022

ABSTRACTEarly independence is a crucial stage in the ontogeny of social environments, but it is often challenging to study in the wild. Genetics may structure groups if young animals associate with familiar kin, but association opportunities also develop as a by-product of environmental processes such as spatial resource distribution. The contribution of these alternate factors in initial opportunities for bonding outside direct relatives is difficult to pick apart, despite its importance in shaping later life. However, species where genetics and spatial structure are less closely coupled (for example, via extra-pair mating) provide a natural opportunity to disentangle these effects. We addressed this gap by investigating the contribution of relatedness versus spatiotemporal synchrony (natal nest-box location and fledge timing) to early-life social structure in newly-independent young hihi (Notiomystis cincta). We also investigated the contribution of inbreeding in both juveniles and their parents, to individual-level sociality, as this genetic factor has had limited focus in studies of social structure. Using a long-term genetic pedigree, detailed breeding records, and social network data collected across three cohorts, we found that juvenile social associations were predicted by natal nest-box location, irrespective of relatedness between juveniles. Therefore, the physical environment can create initial opportunities for associations to develop once young animals disperse from natal sites. Furthermore, juvenile sociability was predicted by their father’s (but not mother’s) inbreeding, highlighting how genetics may have indirect and intergenerational effects on social behaviour. Overall, social structure in wild animals can emerge early in life if the natal environment determines association opportunities. These patterns may even be pre-determined across generations if breeding and settlement decisions made by parents affect the physical and social environments experienced by their offspring. Ultimately, our study highlights how influences on early life social structure may have important consequences for population dynamics and evolutionary potential.
First molecular phylogeny of the freshwater planarian genus Girardia (Platyelminthes, Tricladida) unveils hidden taxonomic diversity and initiates resolution of its historical biogeography
Authors: Benítez-Álvarez Lisandra , Sluys Ronald , Leal Zanchet Ana María , Leria Laia , Riutort Marta 
Published: July 2022

AbstractThe genus Girardia (Platyhelminthes: Tricladida) comprises several species of which some have spread from their original areas of distribution in the Americas to other parts of the globe. Due to great anatomical similarities between species, morphology-based phylogenetic analyses struggled to resolve the affinities between species and species-groups. This problem is exacerbated by the fact that populations of Girardia may show only asexual reproduction by fissiparity and, thus, do not exhibit a copulatory apparatus, which hampers taxonomic identification and extraction of phylogenetic characters. In the present work this problem has been resolved by constructing a molecular phylogeny of the genus. Although our samples do not include representatives of all known species, they cover a large part of the original distributional range of the genus Girardia. Our phylogenetic results suggest the presence of two main clades, which are genetically and karyologically highly differentiated. North and South American nominal G. tigrina actually constitute two sibling species that are not even closely related. The South American form is here described as a new species. The phylogenetic tree brings to light that Girardia arose on the South American portion of Gondwanaland, from which it, subsequently, dispersed to the Nearctic Region, probably more than once.
Molecular evolution and characterization of domestic duck (Anas platyrynchos) and Goose (Anser indicus) with reference to its wild relatives through whole mitochondrial genome sequencing
Authors: Pal Aruna , Debnath Manti , Chakraborty Argha , Banerjee Samiddha , Pal Abantika 
Published: July 2022

AbstractIt is important to study the evolution and domestication of the domesticated duck (Anas platyrynchos) population from the wide range of wild relatives of Anas spp. Whole mitochondrial genome sequencing was attempted for Anas platyrynchos (Bengal duck) and Anser indicus (goose) from same geographical region. The study deals with the Molecular evolution of domestic duck based on mitochondrial gene due to its sequence variability, and to find out the phylogenetic relationships amongAnas platyrynchosand its wild relatives. In this study we have used 45 wild species of Anas spp to study the mitochondrial genes and phylogenomics. Our result signifies that duck species were effectively discriminated with respect to mitochondrial genes, which could then be used for an appropriate genetic conservation program for the wild duck and domestic duck breeds. The DNA sequences from any unknown sample of the mitochondrial gene may be determined and can compare with those on a DNA database and can do blast for phylogenetic analysis of unknown wild duck, which gives its future scope. In silico analysis for 3D structure forAnas platyrynchoswith the closest relative asAnas poecilorhyncha(Indian spot-billed duck) was attempted.Anas platyrynchoswas also compared withAnser indicus. Therefore, this experiment was conducted to investigate the genetic diversity of West Bengal wild ducks with reference to its wild relatives based on mitochondrial gene.
Low amplitude transcutaneous auricular vagus nerve stimulation modulates performance but not pupil size during non-native speech category learning
Authors: McHaney Jacie R. , Schuerman William L. , Leonard Matthew K. , Chandrasekaran Bharath 
Published: July 2022

AbstractSub-threshold transcutaneous auricular vagus nerve stimulation (taVNS) synchronized with behavioral training can selectively enhance non-native speech category learning in adults. Prior work has demonstrated behavioral performance increases when taVNS is paired with easier-to-learn Mandarin tone categories in native English listeners, relative to when taVNS is paired with harder-to-learn Mandarin tone categories or without taVNS. Mechanistically, this temporally-precise plasticity has been attributed to noradrenergic modulation. However, prior work did not specifically utilize methodologies that indexed noradrenergic modulation and, therefore, were unable to explicitly test this hypothesis. Our goals for the current study were to use pupillometry to gain mechanistic insights into taVNS behavioral effects. Participants learned to categorize Mandarin tones while pupillometry was recorded. In a double-blind design, participants were divided into two taVNS groups that, as in the prior study, differed according to whether taVNS was paired with easier-to-learn tones or harder-to-learn tones. We found that taVNS led to faster rates of learning on trials paired with stimulation. Lower amplitude taVNS also led to faster rates of learning compared to higher amplitude taVNS. However, these effects were not group specific, and we did not find evidence of a taVNS correlate in the pupillary response. The results suggest that stimulation amplitude may be a critical determinant of learning outcomes and pupillary modulation. Future studies on subthreshold taVNS need to systematically evaluate the effect of stimulation intensity on behavioral plasticity and potential taVNS biomarkers.
Analysis of codon usage and allele frequencies reveal the double-edged nature of cross-kingdom RNAi
Authors: Werner Bernhard T. , Kopp-Schneider Annette , Kogel Karl-Heinz 
Published: July 2022

AbstractBackgroundIn recent years, a new class of small 21- to 24-nt-(s)RNAs has been discovered from microbial pathogens that interfere with their host’s gene expression during infection, reducing the host’s defence in a process called cross-kingdom RNA interference (ckRNAi). According to this model, microbial sRNAs should exert selection pressure on plants so that gene sequences that reduce complementarity to sRNAs are preferred. In this paper, we test this consequence of the ckRNA model by analyzing changes to target sequences considering codon usage and allele frequencies in the model system Arabidopsis thaliana (At) – Hyaloperonospora arabidopsidis (Ha) and Hordeum vulgare (Hv) – Fusarium graminearum (Fg). In both pathosystems, some selected sRNA and their corresponding target have been described and experimentally validated, while the lengthy methodology prevents the analysis of all discovered sRNAs. To expand the understanding of ckRNAi, we apply a new in silico approach that integrates the majority of sRNAs.ResultsWe calculated the probability (PCHS) that synonymous host plant codons in a predicted sRNA target region would show the same or stronger complementarity as actually observed and compared this probability to sets of virtual analogous sRNAs. For the sets of Ha and Fg sRNAs, there was a significant difference in codon usage in their plant gene target regions (for Ha: PCHS 24.9% lower than in the virtual sets; for Fg: PCHS 19.3% lower than in the virtual sets), but unexpectedly for both sets of microbial sRNA we found a tendency towards codons with an unexpectedly high complementarity. To distinguish between complementarity caused by balancing sRNA-gene coevolution and directional selection we estimated Wright’s F-statistic (FST), a measurement of population structure, in which positive deviations from the background indicate directional and negative deviations balancing selection at the respective loci. We found a negative correlation between PCHS and FST (p=0.03) in the At-Ha system indicating deviations from codon usage favoring complementarity are generally directionally selected.ConclusionThe directional selection of complementary codons in host plants suggests an evolutionary pressure to facilitate silencing by exogenous microbial sRNAs, which is not consistent with the anticipated biological role of pathogen sRNAs as exclusively effectors in cross-kingdom RNAi. To resolve this conflict, we propose an extended model in which microbial sRNAs are perceived by plants via RNA interference and, via coevolution, primarily help to fine-tune plant gene expression.
Operationalizing climate risk in a global warming hotspot
Authors: Boyce Daniel G. , Tittensor Derek P. , Fuller Susanna , Henson Stephanie , Kaschner Kristen , Reygondeau Gabriel , Schleit Kathryn E. , Saba Vincent , Shackell Nancy , Stanley Ryan , Worm Boris 
Published: July 2022

AbstractThere has been a proliferation of climate change vulnerability assessments of species, yet possibly due to their limited reproducibility, scalability, and interpretability, their operational use in applied decision-making remains paradoxically low. We use a newly developed Climate Risk Index for Biodiversity to evaluate the climate vulnerability and risk for ∼2,000 species across three ecosystems and 90 fish stocks in the northwest Atlantic Ocean, a documented global warming hotspot. We found that harvested and commercially valuable species were at significantly greater risk of exposure to hazardous climate conditions than non-harvested species, and emissions mitigation disproportionately reduced their projected exposure risk and cumulative climate risk. Of the 90 fish stocks we evaluated, 41% were at high climate risk, but this proportion dropped to 25% under emissions mitigation. Our structured framework demonstrates how climate risk can be operationalized to support short- and long-term fisheries objectives to enhance marine fisheries’ climate readiness and resilience.
Single cell transcriptomic landscapes of human liver organoids stratify models of non-alcoholic fatty liver disease
Authors: Hess Anja , Gentile Stefan D. , Saad Amel Ben , Rahman Raza-Ur , Habboub Tim , Mullen Alan C. 
Published: July 2022

SummaryNon-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of morbidity with few treatment options available. Thus, accuratein vitrosystems to test new therapies are indispensable. Recently, human liver organoid (HLO) NAFLD models have emerged. However, a systematic evaluation of their translational potential is currently missing. Here, we develop a structured approach to evaluate NAFLD-HLO models, testing oleic acid (OA) and palmitic acid (PA) in comparison to TGF-β1 for disease induction. Through analysis of ∼100K single-cell transcriptomes of the HLO injury landscape, we find all three models induce inflammatory signatures. However, only TGF-β1 promotes collagen production, fibrosis, and hepatic stellate cell (HSC) expansion. In striking contrast, OA ameliorates fibrotic signatures and reduces the HSC population. Integrating data from each model with that of NAFLD patients across disease progression further demonstrates PA and TGF-β1 more robustly model inflammation and fibrosis. Our findings highlight the importance to stratify NAFLD-HLO models by clinical disease progression, provide a single-cell reference to benchmark future organoid injury models, and allow us to study evolving steatohepatitis, fibrosis, and HSC susceptibility to injury in a dynamic, multi-lineage humanin vitrosystem.
Emergence of a proton exchange-based isomerization and lactonization mechanism in the plant coumarin synthase COSY
Authors: Kim Colin Y. , Mitchell Andrew J. , Kastner David W. , Albright Claire E. , Gutierrez Michael , Glinkerman Christopher M. , Kulik Heather J. , Weng Jing-Ke 
Published: July 2022

AbstractPlants contain rapidly evolving specialized metabolic enzymes to support the synthesis of a myriad of functionally diverse natural products. In the case of coumarin biosynthesis, a BAHD acyltransferase-family enzyme COSY was recently discovered in Arabidopsis that catalyzes coumarin formation fromo-hydroxylatedtrans-hydroxycinnamoyl-CoA substrates. COSY is the first and only BAHD enzyme known to date that catalyzes an intramolecular acyl transfer reaction. Here we combine structural, biochemical, and computational approaches to investigate the mechanistic basis for the unique coumarin synthase activity of COSY. Comparative analyses of crystal structures ofArabidopsis thalianaCOSY relative to other BAHD proteins reveal that COSY possesses an unconventional active-site configuration adapted to its specialized activity. Through deuterium exchange experiments, we discover a unique proton exchange mechanism at the α-carbon of theo-hydroxylatedtrans-hydroxycinnamoyl-CoA substrates during the catalytic cycle of COSY. Mutagenesis studies and quantum mechanical cluster modeling further support that this mechanism is key to COSY’s ability to lower the activation energy of thetrans-to-cisisomerization of the hydroxycinnamoyl-CoA substrates, a critical rate-limiting step leading to coumarin production. This study unveils the emergence of an unconventional catalytic mechanism mediated by a BAHD-family enzyme, and sheds light on the potential evolutionary origin of COSY and its recruitment to the evolutionarily new coumarin biosynthetic pathway in eudicots.