bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural foundations of potassium selectivity in channelrhodopsins
Authors: Govorunova Elena G. , Sineshchekov Oleg A. , Brown Leonid S. , Bondar Ana-Nicoleta , Spudich John L. 
Published: September 2022

ABSTRACTKalium channelrhodopsins (KCRs) are light-gated K+ channels recently found in the stramenopile protist Hyphochytrium catenoides. When expressed in neurons, KCRs enable high-precision optical inhibition of spiking (optogenetic silencing). KCRs are capable of discriminating K+ from Na+ without the conventional K+-selectivity filter found in classical K+ channels. The genome of H. catenoides also encodes a third paralog that is more permeable for Na+ than for K+. To identify structural motifs responsible for the unusual K+ selectivity of KCRs, we systematically analyzed a series of chimeras and mutants of this protein. We found that mutations of three critical residues in the paralog convert its Na+ selective channel into a K+ selective one. Our characterization of homologous proteins from other protists (Colponema vietnamica, Cafeteria burkhardae and Chromera velia) and metagenomic samples confirmed the importance of these residues for K+ selectivity. We also show that Trp102 and Asp116, conserved in all three H. catenoides orthologs, are necessary, although not sufficient, for K+ selectivity. Our results provide the foundation for further engineering of KCRs for optogenetic needs.IMPORTANCERecently discovered microbial light-gated ion channels (channelrhodopsins) with a higher permeability for K+ than for Na+ (kalium channelrhodopsins, or KCRs) demonstrate an alternative K+ selectivity mechanism, unrelated to well-characterized “selectivity filters” of voltage- and ligand-gated K+ channels. KCRs can be used for optogenetic inhibition of neuronal firing, and potentially for the development of gene therapies to treat neurological and cardiovascular disorders. In this study we identify structural motifs that determine the K+ selectivity of KCRs that provide the foundation for that provide the foundation for elucidating their K+ selectivity mechanism and for their further engineering as optogenetic tools.
SARS-CoV-2 Uses Nonstructural Protein 16 to Evade Restriction by IFIT1 and IFIT3
Authors: Schindewolf Craig , Lokugamage Kumari , Vu Michelle N. , Johnson Bryan A. , Scharton Dionna , Plante Jessica A. , Kalveram Birte , Crocquet-Valdes Patricia A. , Sotcheff Stephanea , Jaworski Elizabeth , Alvarado R. Elias , Debbink Kari , Daugherty Matthew D. , Weaver Scott C. , Routh Andrew L. , Walker David H. , Plante Kenneth S. , Menachery Vineet D. 
Published: September 2022

AbstractUnderstanding the molecular basis of innate immune evasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important consideration for designing the next wave of therapeutics. Here, we investigate the role of the nonstructural protein 16 (NSP16) of SARS-CoV-2 in infection and pathogenesis. NSP16, a ribonucleoside 2’-O methyltransferase (MTase), catalyzes the transfer of a methyl group to mRNA as part of the capping process. Based on observations with other CoVs, we hypothesized that NSP16 2’-O MTase function protects SARS-CoV-2 from cap-sensing host restriction. Therefore, we engineered SARS-CoV-2 with a mutation that disrupts a conserved residue in the active site of NSP16. We subsequently show that this mutant is attenuated both in vitro and in vivo, using a hamster model of SARS-CoV-2 infection. Mechanistically, we confirm that the NSP16 mutant is more sensitive to type I interferon (IFN-I) in vitro. Furthermore, silencing IFIT1 or IFIT3, IFN-stimulated genes that sense a lack of 2’-O methylation, partially restores fitness to the NSP16 mutant. Finally, we demonstrate that sinefungin, a methyltransferase inhibitor that binds the catalytic site of NSP16, sensitizes wild-type SARS-CoV-2 to IFN-I treatment. Overall, our findings highlight the importance of SARS-CoV-2 NSP16 in evading host innate immunity and suggest a possible target for future antiviral therapies.ImportanceSimilar to other coronaviruses, disruption of SARS-CoV-2 NSP16 function attenuates viral replication in a type I interferon-dependent manner. In vivo, our results show reduced disease and viral replication at late times in the hamster lung, but an earlier titer deficit for the NSP16 mutant (dNSP16) in the upper airway. In addition, our results confirm a role for IFIT1, but also demonstrate the necessity of IFIT3 in mediating dNSP16 attenuation. Finally, we show that targeting NSP16 activity with a 2’-O methyltransferase inhibitor in combination with type I interferon offers a novel avenue for antiviral development.
A natural history of networks: Modeling higher-order interactions in geohistorical data
Authors: Rojas Alexis , Holmgren Anton , Neuman Magnus , Edler Daniel , Blöcker Christopher , Rosvall Martin 
Published: September 2022

AbstractPaleobiologists are increasingly employing network-based methods to analyze the complex data retrieved from geohistorical records, including stratigraphic sections, sediments, and fossil collections. However, the lack of a common framework for designing, performing, evaluating, and communicating these studies, leads to issues of reproducibility and communicability. The high-dimensional geohistorical data also raises questions about the limitations of standard network approaches, which assume independent interactions between pairs of components. Higher-order network models better suited for the complex relational structure of the geohistorical data provide an opportunity to overcome these challenges. These models can represent temporal and spatial constraints inherent to the biosedimentary record and describe higher-order interactions, capturing more accurate biogeographical, biostratigraphic, and macroevolutionary patterns. Here we describe how to use the Map Equation framework for designing higher-order network models of geohistorical data, address some practical decisions involved in modeling complex dependencies, and discuss critical methodological and conceptual issues that currently make it difficult to compare results across studies in the growing body of network-based paleobiology research. We illustrate different higher-order network representations and models, including multilayers, hypergraphs, and varying Markov times models, using case studies on gradient analysis, bioregionalization, and macroevolution, and delineate future research directions for current challenges in the emerging field of network paleobiology.
Somatostatin slows Aβ plaque deposition in aged APPNL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner
Authors: Williams Declan , Yan Bei Qi , Wang Hansen , Negm Logine , Sackmann Christopher , Verkuyl Claire , Rezai-Stevens Vanessa , Eid Shehab , Sato Christine , Watts Joel C. , Wille Holger , Schmitt-Ulms Gerold 
Published: September 2022

ABSTRACTThe molecular underpinnings that govern the endoproteolytic release of the amyloid beta peptide (Aβ) from the amyloid precursor protein (APP) are now quite well understood. The same cannot be said for the events that precipitate the aggregation and amyloid deposition of Aβ in Alzheimer’s disease (AD). The 14-amino-acid cyclic neuroendocrine peptide somatostatin (SST-14) has long been thought of as playing a role, foremost by controlling the expression of the Aβ clearing enzyme neprilysin, and more recently by directly interacting with Aβ oligomers. Missing have been in vivo data in a relevant Aβ amyloidosis model. Here we addressed this shortcoming by crossing AppNL-F/NL-F mice with Sst-deficient mice of identical genetic background to assess if and how the presence of Sst influences key pathological hallmarks of Aβ amyloidosis that develop in AppNL-F/NL-F mice after 10 months of age. Surprisingly, we found that Sst had no influence on whole brain neprilysin transcript, protein or activity levels, an observation that cannot be accounted for by a compensatory upregulation of the Sst paralog, cortistatin (Cort), that we observed in 15-month-old Sst-deficient mice. The absence of Sst did lead to a subtle but significant increase in the density of cortical Aβ amyloid plaques. Follow-on western blot analyses of whole brain extracts indicated that Sst interferes with early steps of Aβ assembly that manifest in Sst null brains through the appearance of SDS-stable smears of 55- 150 kDa. As expected, no effect of Sst on tau steady-state levels or its phosphorylation were observed. Results from this study are easier reconciled with an emerging body of data that point toward Sst affecting Aβ amyloid plaque formation through direct interference with Aβ aggregation rather than through its effects on neprilysin expression.
3D Ground Truth Annotations of Nuclei in 3D Microscopy Volumes
Authors: Chen Alain , Wu Liming , Winfree Seth , Dunn Kenneth W. , Salama Paul , Delp Edward J. 
Published: September 2022

ABSTRACTIn this paper we describe a set of 3D microscopy volumes we have partially manually annotated. We describe the volumes annotated and the tools and processes we use to annotate the volumes. In addition, we provide examples of annotated subvolumes. We also provide synthetically generated 3D microscopy volumes that can be used for training segmentation methods. The full set of annotations, synthetically generated volumes, and original volumes can be accessed as described in the paper.
Evaluating user experience with immersive technology in simulation-based education: a modified Delphi study with qualitative analysis
Authors: Jacobs Chris , Foote Georgia , Williams Michael 
Published: September 2022

AbstractBackgroundImmersive technology is becoming more widespread in simulation-based medical education with applications that both supplement and replace traditional teaching methods. There is a lack of validated measures that capture user experience to inform of the technology utility. We aimed to establish a consensus of items and domains that different simulation experts would include in a measure for immersive technology use.MethodsA 3-stage modified Delphi using online software was conducted to support the conceptual framework for the proposed measure. The first round was informed by prior work on immersive technology in simulation. In the first round, participants were asked to describe what we could measure in simulation-based education and technology. Thematic analysis generated key themes that were presented to the participants in the second round. Ranking of importance in round 2 was determined by mean rank scores. The final round was an online meeting for final consensus discussion and most important domains by experts were considered.ResultsA total of 16 simulation experts participated in the study. A consensus was reached on the ideal measure in immersive technology simulation that would be a user questionnaire and domains of interest would be: what was learnt, the degree of immersion experienced, fidelity provided, debrief, psychological safety and patient safety. No consensus was reached with the barriers that this technology introduces in education.ConclusionsThere is varied opinion on what we should prioritise in measuring the experience in simulation practice. Importantly, this study identified key areas that aids our understanding on how we can measure new technology in educational settings. Synthesising these results in to a multidomain instrument requires a systematic approach to testing in future research
Genome-scale mRNA transcriptomic insights into the mature growth dynamic of Cigar tobacco leaves
Authors: Yang Jinpeng , Wan Di , Qiao Baoming , Yu Jun , Li Zongping , Liu Daisong , Lv Peijun , Hu Jinwen , Rao Xiongfei , Xu Fangsen , Wang Sheliang , Yang Chunlei 
Published: September 2022

AbstractThe harvest time is a key factor for cigar leaves with high quality, which varies greatly depending on the environment. Here, we performed a genome-scale mRNA transcriptomic analysis on the cigar cultivar CX-26 (Nicotiana tabacum L.) to evaluate the relationship between gene expression and growth state. The leaves were harvested with 67 (T1), 71(T2) and 75 (T3)-day growth. A total of 80,502 genes were detected in the CX-26 leaves, of which 64,611 genes were annotated on the reference genome. Principal component analysis showed that T1 and T2 leaves had a high overlapping pattern, while T3 leaves were distinct. Indeed, T1 and T2 leaves had fewer differential expressing genes (DEGs), while T3 leaves had 26,456 DGEs from T2 leaves, supporting the distinct growth of T3 leaves. GO annotations mainly enriched the photosynthesis-related metabolic process, catalytic activity and binding biological processes. KEEG analysis identified the key pathways including photosynthesisantenna proteins, plant hormone/MAPK signaling pathway and plant-pathogen interaction. The maturity regulation and defense response-associated hormones abscisic acid and jasmonate acid were higher in the T3 leaves than that in T1 and T2 leaves confirming the KEEG analysis. Furthermore, several photosynthesis-related enzymes and a transcription factor were highlighted in the gene regulatory network, which might regulate the dynamics of carbohydrate metabolism, lipid metabolism and energy metabolism. In summary, our study provides insight into the growth state of CX-26 cigar leaves.
Updated site concordance factors minimize effects of homoplasy and taxon sampling
Authors: Mo Yu K. , Lanfear Robert , Hahn Matthew W. , Minh Bui Quang 
Published: September 2022

AbstractMotivationSite concordance factors (sCFs) have become a widely used way to summarize discordance in phylogenomic datasets. However, the original version of sCFs were calculated by sampling a quartet of tip taxa and then applying parsimony-based criteria for discordance. This approach has the potential to be strongly affected by multiple hits at a site (homoplasy), especially when substitution rates are high or taxa are not closely related.ResultsHere, we introduce a new method for calculating site concordance factors. The updated version uses likelihood to generate probability distributions of ancestral states at internal nodes of the phylogeny. By sampling from the states at internal nodes adjacent to a given branch, this approach substantially reduces—but does not completely abolish—the effects of homoplasy and taxon sampling.Availability and implementationUpdated sCFs are implemented in IQ-TREE 2.2.2. The software is freely available at https://github.com/iqtree/iqtree2/releases.Contactmoyu@iu.edu
An Aurora B-RPA signaling axis secures chromosome segregation fidelity
Authors: Roshan Poonam , Kuppa Sahiti , Mattice Jenna R. , Kaushik Vikas , Chadda Rahul , Pokhrel Nilisha , Tumala Brunda , Bothner Brian , Antony Edwin , Origanti Sofia 
Published: September 2022

AbstractErrors in chromosome segregation underlie genomic instability associated with cancers. Resolution of replication and recombination intermediates and protection of vulnerable single-stranded DNA (ssDNA) intermediates during mitotic progression requires the ssDNA binding protein Replication Protein A (RPA). However, the mechanisms that regulate RPA specifically during unperturbed mitotic progression are poorly resolved. RPA is a heterotrimer composed of RPA70, RPA32 and RPA14 subunits and is predominantly regulated through hyperphosphorylation of RPA32 in response to DNA damage. Here, we have uncovered a mitosis-specific regulation of RPA by Aurora B kinase. Aurora B phosphorylates Ser-384 in the DNA binding domain B of the large RPA70 subunit and highlights a mode of regulation distinct from RPA32. Disruption of phosphorylation markedly affects cell viability and causes defects in chromosome segregation with hypersensitivity to DNA damaging agents. Phosphorylation at Ser-384 remodels the protein interaction domains of RPA and facilitates formation of higher density filaments. Furthermore, phosphorylation impairs RPA binding to DSS1 that likely suppresses homologous recombination during mitosis by preventing recruitment of DSS1-BRCA2 to exposed ssDNA. We showcase a critical RPA-Aurora B signaling axis in mitosis that is essential for maintaining genomic integrity.
Perturbation variance suppresses error sensitivity in the implicit learning system
Authors: Albert Scott , Shadmehr Reza 
Published: September 2022

AbstractWhen variability is added to a sensorimotor perturbation, total adaptation is impaired. In Albert et al.1 we explored this phenomenon, and observed that it is the brain’s implicit, i.e., subconscious learning system that is most affected by perturbation variance. We observed that perturbation variability impaired implicit learning by downregulating its sensitivity to error. Recently, Wang et al.2 present an alternate viewpoint: implicit error sensitivity does not change with experience, only the errors observed by the implicit system change. Here we evaluated this alternate view by empirically measuring error sensitivity as a function of error size. We found that perturbation variability strongly downregulates implicit error sensitivity when controlling for error size, consistent with our original results, counter to the inflexible model argued by Wang et al. With that said, a pre-existing relationship between error sensitivity and error magnitude noted by Wang et al. can contribute at least in part to implicit behavior. State-space models that start with this pre-existing error sensitivity curve and then update it with training according to a ‘memory of errors’ most accurately tracked measured behavior.
A scalable implementation of the recursive least-squares algorithm for training spiking neural networks
Authors: Arthur Benjamin J. , Kim Christopher M. , Chen Susu , Preibisch Stephan , Darshan Ran 
Published: September 2022

AbstractTraining spiking recurrent neural networks on neuronal recordings or behavioral tasks has become a popular way to study computations performed by the nervous system. As the size and complexity of neural recordings increase, there is a need for efficient algorithms that can train models in a short period of time using minimal resources. We present optimized CPU and GPU implementations of the recursive least-squares algorithm in spiking neural networks. The GPU implementation can train networks of one million neurons, with 100 million plastic synapses and a billion static synapses, about 1000 times faster than an unoptimized reference CPU implementation. We demonstrate the code’s utility by training a network, in less than an hour, to reproduce the activity of > 66, 000 recorded neurons of a mouse performing a decision-making task. The fast implementation enables a more interactivein-silicostudy of the dynamics and connectivity underlying multi-area computations. It also admits the possibility to train models asin-vivoexperiments are being conducted, thus closing the loop between modeling and experiments.
Fine-scale sampling uncovers the complexity of migrations in 5th-6th century Pannonia
Authors: Vyas Deven N. , Koncz István , Modi Alessandra , Mende Balázs Gusztáv , Tian Yijie , Francalacci Paolo , Lari Martina , Vai Stefania , Straub Péter , Gallina Zsolt , Szeniczey Tamás , Hajdu Tamás , Radzevičiūtė Rita , Hofmanová Zuzana , Évinger Sándor , Bernert Zsolt , Pohl Walter , Caramelli David , Vida Tivadar , Geary Patrick J. , Veeramah Krishna R. 
Published: September 2022

SummaryAs the collapse of the Western Roman Empire accelerated during the 4th and 5th centuries, arriving “barbarian” groups began to establish new communities in the border provinces of the declining (and eventually former) empire. This was a time of significant cultural and political change throughout not only these border regions but Europe as a whole.1,2To better understand post-Roman community formation in one of these key frontier zones after the collapse of the Hunnic movement, we generated new paleogenomic data for a set of 38 burials from a time series of three 5th century cemeteries3–5at Lake Balaton, Hungary. We utilized a comprehensive sampling approach to characterize these cemeteries along with data from 38 additional burials from a previously published mid-6th century site6and analyzed them alongside data from over 550 penecontemporaneous individuals7–19. The range of genetic diversity in all four of these local burial communities is extensive and wider ranging than penecontemporaneous Europeans sequenced to date. Despite many commonalities in burial representation and demography, we find that there were substantial differences in genetic ancestry between the sites. We detect evidence of northern European gene flow into the Lake Balaton region. Additionally, we observe a statistically significant association between dress artefacts and genetic ancestry among 5th century genetically female burials. Our analysis shows that the formation of early Medieval communities was a multifarious process even at a local level, consisting of genetically heterogeneous groups.
Comparison Of New and emerging SARS-CoV-2 variant Transmissibility through Active Contact Testing. A comparative cross-sectional household seroprevalence study
Authors: Gaskell KM , Kheir N El , Mirfendesky M , Rampling T , Marks M , Houlihan C F , Lemonge N , Bristowe H , Aslam S , Kyprianou D , Nastouli E , Goldblatt D , Fielding K , Moore DAJ ,   CONTACT team (field team)
Published: September 2022

AbstractHistorically SARS-CoV-2 secondary attack rates (SAR) have been based on PCR positivity on screening symptomatic contacts, this misses transmission events and identifies only symptomatic contacts who are PCR positive at the time of sampling. We used serology to detect the relative transmissibility of Alpha Variant of Concern (VOC) to non-VOC SARS-CoV-2 to calculate household secondary attack rates. We identified index patients diagnosed with Alpha and non-VOC SARS-CoV-2 across two London Hospitals between November 2020 and January 2021 during a prolonged and well adhered national lockdown. We completed a household seroprevalence survey and found that 61.8% of non-VOC exposed household contacts were seropositive compared to 82.1% of Alpha exposed household contacts. The odds of infection doubled with exposure to an index diagnosed with Alpha. There was evidence of transmission events in almost all households. Our data strongly support that estimates of SAR should include serological data to improve accuracy and understanding.Key MessagesSecondary attack rates (SAR) in SARS-CoV-2 were previously calculated using PCR positive samples only, it is more accurate to use a household transmission model and screen contacts using serology, as done in this study. SAR should include serological data to improve accuracy and understanding. All households in this study had transmission events. SAR were 61.8% in non-VOC SARS-CoV-2 exposed household contacts compared to 82.1% in Alpha SARS-CoV-2 exposed household contacts.