bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remdesivir to treat COVID-19: can dosing be optimized?
Authors: Conway Jessica M. , zur Wiesch Pia Abel 
Published: June 2021

AbstractThe antiviral remdesivir has been approved by regulatory bodies such as EMA and FDA for the treatment of COVID-19. However, its efficacy is debated and toxicity concerns might limit the therapeutic range of this drug. Computational models that aid in balancing efficacy and toxicity would be of great help. Parametrizing models is difficult because the prodrug remdesivir is metabolized to its active form (RDV-TP) upon cell entry, which complicates dose-activity relationships.Here, we employ a computational model that allows predicting drug efficacy based on the binding affinity of RDV-TP for its target polymerase in SARS-CoV-2. We identify an optimal infusion rate to maximize remdesivir efficacy. We also assess drug efficacy in suppressing both wild-type and resistant strains, and thereby selection of resistance.Our results differ from predictions using prodrug dose-response curves (pseudo-EC50s). We expect that reaching 90% inhibition (EC90) is insufficient to suppress SARS-CoV-2 in lungs. While standard dosing mildly inhibits viral polymerase and therefore likely reduces morbidity, we also expect selection for resistant mutants for most realistic parameter ranges. To increase efficacy and safeguard against resistance, we recommend continuing remdesivir use with companion antivirals and/or with dosing regimens that substantially increase the levels of RDV-TP.
Massive social protests amid the pandemic in selected Colombian cities: Did they increase COVID-19 cases?
Authors: Moreno-Montoya José , Rodríguez-Villamizar Laura A. , Idrovo Alvaro J. 
Published: June 2021

AbstractBackgroundSince April 28, 2021, in Colombia there are social protests with numerous demonstrations in various cities. The aim of this study was to assess the effect of social protests on the number and trend of the confirmed COVID-19 cases in some selected Colombian cities where social protests had more intensity.MethodsWe performed and interrupted time-series analysis (ITSA) and Autoregressive Integrated Moving Average (ARIMA) models, based on the confirmed COVID-19 cases in Colombia, between March 1 and May 15, 2021, for Bogotá, Cali, Barranquilla, Medellín, and Bucaramanga. The ITSA models estimated the effect of social demonstrations on the number and trend of cases for each city by using Newey-West standard errors. ARIMA models assessed the overall pattern of the series and effect of the intervention. We considered May 2, 2021, as the intervention date for the analysis, five days after social demonstrations started in the country.FindingsDuring the study period the number of cases by city was 1,014,815 for Bogotá, 192,320 for Cali, 175,269 for Barranquilla, 311,904 for Medellín, and 62,512 for Bucaramanga. Heterogeneous results were found among cities. Only for the cities of Cali and Barranquilla statistically significant changes in trend of the number of cases were obtained after the intervention: positive in the first city, negative in the second one. None ARIMA models show evidence of abrupt changes in the trend of the series for any city and intervention effect was only significant for Bucaramanga.InterpretationSocial protests had a heterogeneous effect on the number and trend of COVID-19 cases. Different effects might be related to the epidemiologic moment of the pandemic and the characteristics of the social protests. Assessing the effect of social protests within a pandemic is complex and there are several methodological limitations. Further analyses are required with longer time-series data.
Classification and Visualisation of Normal and Abnormal Radiographs; a comparison between Eleven Convolutional Neural Network Architectures
Authors: Ananda Ananda , Ngan Kwun Ho , Karabağ Cefa , Ter-Sarkisov Aram , Alonso Eduardo , Reyes-Aldasoro Constantino Carlos 
Published: June 2021

AbstractThis paper investigates the classification of radiographic images with eleven convolutional neural network (CNN) architectures (GoogleNet, VGG-19, AlexNet, SqueezeNet, ResNet-18, Inception-v3, ResNet-50, VGG-16, ResNet-101, DenseNet-201 and Inception-ResNet-v2). The CNNs were used to classify a series of wrist radiographs from the Stanford Musculoskeletal Radiographs (MURA) dataset into two classes - normal and abnormal. The architectures were compared for different hyper-parameters against accuracy and Cohen’s kappa coefficient. The best two results were then explored with data augmentation. Without the use of augmentation, the best results were provided by Inception-Resnet-v2 (Mean accuracy = 0.723, Mean kappa = 0.506). These were significantly improved with augmentation to Inception-Resnet-v2 (Mean accuracy = 0.857, Mean kappa = 0.703). Finally, Class Activation Mapping was applied to interpret activation of the network against the location of an anomaly in the radiographs.
Defining protein variant functions using high-complexity mutagenesis libraries and enhanced mutant detection software ASMv1.0
Authors: Yang Xiaoping , Hong Andrew L. , Sharpe Ted , Giacomelli Andrew O. , Lintner Robert E. , Alan Douglas , Green Thomas , Hayes Tikvah K. , Piccioni Federica , Fritchman Briana , Kawabe Hinako , Sawyer Edith , Sprenkle Luke , Lee Benjamin P. , Persky Nicole S. , Brown Adam , Greulich Heidi , Aguirre Andrew J. , Meyerson Matthew , Hahn William C. , Johannessen Cory M. , Root David E. 
Published: June 2021

AbstractPooled variant expression libraries can test the phenotypes of thousands of variants of a gene in a single multiplexed experiment. In a library encoding all single-amino-acid substitutions of a protein, each variant differs from its reference only at a single codon-position located anywhere along the coding sequence. Consequently, accurately identifying these variants by sequencing is a major technical challenge. A popular but expensive brute-force approach is to divide the pool of variants into multiple smaller sub-libraries that each contains variants of a small region and that must each be constructed and screened individually, but that can then be PCR-amplified and fully sequenced with a single read to allow direct readout of variant abundance. Here we present an approach to screen very large variant libraries with mutations spanning a wide region in a single pool, including library design criteria and mutant-detection algorithms that permit reliable calling and counting of variants from large-scale sequencing data.
Properties of Two-Locus Genealogies and Linkage Disequilibrium in Temporally Structured Samples
Authors: Biddanda Arjun , Steinrücken Matthias , Novembre John 
Published: June 2021

AbstractArchaeogenetics has been revolutionary, revealing insights into demographic history and recent positive selection in many organisms. However, most studies to date have ignored the non-random association of genetic variants at different loci (i.e., linkage disequilibrium, LD). This may be in part because basic properties of LD in samples from different times are still not well understood. Here, we derive several results for summary statistics of haplotypic variation under a model with time-stratified sampling: 1) The correlation between the number of pairwise differences observed between time-staggered samples (πΔt) in models with and without strict population continuity; 2) The product of the LD coefficient, D, between ancient and modern samples, which is a measure of haplotypic similarity between modern and ancient samples; and 3) The expected switch rate in the Li and Stephens haplotype copying model. The latter has implications for genotype imputation and phasing in ancient samples with modern reference panels. Overall, these results provide a characterization of how haplotype patterns are affected by sample age, recombination rates, and population sizes. We expect these results will help guide the interpretation and analysis of haplotype data from ancient and modern samples.
Biogenesis of hepatitis B virus e antigen is driven by translocon-associated protein complex and regulated by conserved cysteines in signal peptide
Authors: Zábranská Helena , Zábranský Aleš , Lubyová Barbora , Hodek Jan , Křenková Alena , Hubálek Martin , Weber Jan , Pichová Iva 
Published: June 2021

AbstractHepatitis B virus (HBV) uses e antigen (HBe), which is dispensable for virus infectivity, to modulate host immune responses and achieve viral persistence in human hepatocytes. The HBe precursor (p25) is directed to the endoplasmic reticulum (ER), where cleavage of the signal peptide (sp) gives rise to the first processing product, p22. P22 can be retro-translocated back to the cytosol or enter the secretory pathway and undergo a second cleavage event, resulting in secreted p17 (HBe). Here, we report that translocation of p25 to the ER is promoted by translocon-associated protein complex (TRAP). We found that p25 is not completely translocated into the ER; a fraction of p25 is phosphorylated and remains in the cytoplasm and nucleus. Within the p25 sp sequence, we identified three cysteine residues that control the efficiency of sp cleavage and contribute to proper subcellular distribution of the precore pool.
School yard biodiversity determines short-term recovery of disturbed skin microbiota in children
Authors: Mills Jacob G. , Selway Caitlin A. , Thomas Torsten , Weyrich Laura S. , Lowe Andrew J. 
Published: June 2021

AbstractThe planting and conservation of biodiverse habitat in urban contexts has been proposed as a public health intervention aimed at reducing the prevalence of non-communicable diseases via microbiome rewilding (Mills et al. 2017; Mills et al. 2019). However, our understanding of the effect of urban biodiversity interventions on the human microbiota remains limited, especially on the skin (Hui et al. 2019; Roslund et al. 2020) and in the context of permanent green spaces (Lehtimäki et al. 2018; Selway et al. 2020). Here, we test the short-term response of experimentally disturbed bacterial communities on the skin of healthy children exposed to different school environments – either a ‘classroom’, a ‘sports field’, or a biodiverse ‘forest’ – to understand how exposures to different types of biodiversity may influence skin microbiota. Children exposed to the ‘forest’ had significantly increased skin microbiota diversity when compared to pre-exposure, an effect that increased over three days suggesting long-term effects. The microbiota on children exposed to the ‘forest’ had the largest structural and compositional community change compared to children exposed to ‘sports fields’, which in turn was larger than those who remained in ‘classrooms’. Children exposed to ‘sports fields’ and ‘forests’ also acquired new core bacteria after exposure to green spaces, potentially buffering against disturbances to the skin microbiota’s diversity, while individuals who remained in the ‘classroom’ lost microbes throughout the experiment. Overall, we conclude that urban green spaces can have an enriching influence on the diversity of skin microbiota, including core members shared between all children. These findings have important implications for the design and construction of new school yards and public spaces with respect to biodiversity, health, and human microbiota.
Introgression of type-IV glandular trichomes from Solanum galapagense to cultivated tomato reveals genetic complexity for the development of acylsugar-based insect resistance
Authors: Vendemiatti Eloisa , Therezan Rodrigo , Vicente Mateus H. , de Siqueira Pinto Maísa , Bergau Nick , Yang Lina , Bernardi Walter Fernando , de Alencar Severino M. , Zsögön Agustin , Tissier Alain , Benedito Vagner A. , Peres Lázaro E. P. 
Published: June 2021

SummaryGlandular trichomes are involved in the production of food- and medicine-relevant chemicals in plants, besides being associated with pest resistance. In some wild Solanum species closely related to the cultivated tomato (S. lycopersicum), the presence of type-IV glandular trichomes leads to the production of high levels of insecticide acylsugars (AS). Conversely, low AS production observed in the cultivated tomato is attributed to its incapacity to develop type-IV trichomes in adult organs. Therefore, we hypothesized that cultivated tomatoes engineered to harbor type-IV trichomes on the leaves of mature plants can be pest resistant. We introgressed into the tomato cultivar Micro-Tom (MT) the capability of S. galapagense to maintain the development of type-IV trichomes throughout all plant stages, thus creating a line named “Galapagos enhanced trichomes” (MT-Get). Mapping-by-sequencing of MT-Get revealed that five chromosomal regions of S. galapagense were present in MT-Get. Further mapping reveled that S. galapagense alleles on chromosomes 1, 2 and 3 are sufficient for the presence of type-IV trichomes, but in lower densities. GC-MS, LC-MS, and gene expression analyses demonstrated that the increased density of type-IV trichomes was not accompanied by high AS production and exudation in MT-Get. Moreover, MT-Get did not differ from MT in its susceptibility to whitefly (Bemisia tabaci). Our findings demonstrates that type-IV glandular trichome development along with AS production and exudation are partially uncoupled at the genetic level. The MT-Get genotype represents a valuable resource for further studies involving the biochemical manipulation of type-IV trichome content through either genetic introgression or transgenic approaches.Significance StatementThis work identified loci in the tomato genome that control the heterochronic development of type-IV glandular trichomes and uncoupled the genetic control of this type of trichome ontogeny from acylsugar biosynthesis and accumulation, revealing a higher than anticipated genetic complexity of acylsugar-based insect resistance. The findings reported herein will contribute to further dissect the genetics of trichome development in tomato as well as to introgress broad and durable insect resistance in tomato and other Solanaceae.
RPAP2 regulates a transcription initiation checkpoint by prohibiting assembly of preinitiation complex
Authors: Chen Xizi , Qi Yilun , Wang Xinxin , Wang Zhenning , Wang Li , Song Aixia , Li Jiabei , Zhao Dan , Zhang Hongwei , Jin Qianwei , Chen Fei Xavier , Xu Yanhui 
Published: June 2021

AbstractRNA polymerase II (Pol II)-mediated transcription in metazoan requires precise regulation. RNA polymerase II-associated protein 2 (RPAP2) was previously identified to transport Pol II from cytoplasm to nucleus and dephosphorylates Pol II C-terminal domain (CTD). We found that RPAP2 binds hypo/hyper-phosphorylated Pol II with undetectable phosphatase activity. Structure of RPAP2-Pol II shows mutually exclusive assembly of RPAP2-Pol II and pre-initiation complex (PIC) due to three steric clashes. RPAP2 prevents/disrupts Pol II-TFIIF interaction and impairs in vitro transcription initiation, suggesting a function in prohibiting PIC assembly. Loss of RPAP2 in cells leads to global accumulation of TFIIF and Pol II at promoters, indicating critical role of RPAP2 in inhibiting PIC assembly independent of its putative phosphatase activity. Our study indicates that RPAP2 functions as a gatekeeper to prohibit PIC assembly and transcription initiation and suggests a novel transcription checkpoint.
After traumatic brain injury oligodendrocytes regain a plastic phenotype and can become astrocytes
Authors: Bai Xianshu , Zhao Na , Huang Wenhui , Caudal Laura C. , Zhao Renping , Hirrlinger Johannes , Walz Wolfgang , Kirchhoff Frank , Scheller Anja 
Published: June 2021

AbstractAfter acute brain injuries various response cascades are evoked that direct the formation of the glial scar. Here, we report that acute lesions associated with a disruption of the blood-brain barrier trigger a re-programming within the oligodendrocyte lineage. In PLP-DsRed1/GFAP-EGFP and PLP-EGFPmem/GFAP-mRFP1 transgenic mice with cortical injuries, we transiently found PLP transgene-labelled cells with activated GFAP promoter activity adjacent to the lesion site. We termed them AO cells, based on their concomitant activity of astro- and oligodendroglial genes. By fate mapping using PLP- and GFAP-split Cre complementation and NG2-CreERT2 mice we observed that major portions of AO cells surprisingly differentiated into astrocytes. Using repeated long-term in vivo two-photon laser-scanning microscopy (2P-LSM) we followed oligodendrocytes after injury. We observed their conversion into astrocytes via the AO cell stage with silencing of the PLP promoter and simultaneous activation of the GFAP promoter. In addition, we provide evidence that this oligodendrocyte-to-astrocyte conversion depends on local cues. At the lesion site higher expression levels of various glial differentiation factors were detected. And indeed, local injection of IL-6 promoted the formation of AO cells. In summary, our findings highlight the plastic potential of oligodendrocytes in acute brain trauma. An altered environmental milieu affects gene expression programs of mature oligodendrocytes and induces a plastic differentiation stage with astrogliogenic potential via transitional AO cells.
Probing Affinity, Avidity, Anti-Cooperativity, and Competition in Antibody and Receptor Binding to the SARS-CoV-2 Spike by Single Particle Mass Analyses
Authors: Yin Victor , Lai Szu-Hsueh , Caniels Tom G. , Brouwer Philip J.M. , Brinkkemper Mitch , Aldon Yoann , Liu Hejun , Yuan Meng , Wilson Ian A. , Sanders Rogier W. , van Gils Marit J. , Heck Albert J.R. 
Published: June 2021

AbstractDetermining how antibodies interact with the spike (S) protein of the SARS-CoV-2 virus is critical for combating COVID-19. Structural studies typically employ simplified, truncated constructs that may not fully recapitulate the behaviour of the original complexes. Here, we combine two single particle mass analysis techniques (mass photometry and charge-detection mass spectrometry) to enable measurement of full IgG binding to the trimeric SARS-CoV-2 S ectodomain. Our experiments reveal that antibodies targeting the S-trimer typically prefer stoichiometries lower than the symmetry-predicted 3:1 binding. We determine that this behaviour arises from the interplay of steric clashes and avidity effects that are not reflected in common antibody constructs (i.e. Fabs). Surprisingly, these sub-stoichiometric complexes are fully effective at blocking ACE2 binding despite containing free receptor binding sites. Our results highlight the importance of studying antibody/antigen interactions using complete, multimeric constructs and showcase the utility of single particle mass analyses in unraveling these complex interactions.
Ovipositor and mouthparts in a fossil insect support a novel ecological role for early orthopterans in Pennsylvanian forests
Authors: Chen Lu , Gu Jun-Jie , Yang Qiang , Ren Dong , Blanke Alexander , Béthoux Olivier 
Published: June 2021

ABSTRACTLobeattid insects represented a high portion of the earliest known, Pennsylvanian insect faunas. However, their systematic affinities and their role as foliage feeders which severely influenced their ecosystems remain debated. We investigated hundreds of samples of a new lobeattid species from the Xiaheyan locality using Reflectance Transforming Imaging combined with geometric morphometrics in order to assess its morphology, infer its ecological role, and phylogenetic position.Ctenoptilus frequenssp. nov. possessed a sword-shaped ovipositor whose valves interlocked by two ball-and-socket mechanisms. This unambiguously supports lobeattids as stem-relatives of all Orthoptera (crickets, grasshoppers, katydids). Given the herein presented and other remains, it follows that this group experienced an early diversification coupled with high levels of abundance. The ovipositor shape additionally indicates that ground was the preferred substrate for eggs. Visible mouthparts made it possible to assess the efficiency of the mandibular food uptake system in comparison to a wide array of recent species. The new species was omnivorous which explains the paucity of external damage on contemporaneous plant foliage.
The SAGA core module is critical duringDrosophilaoogenesis and is broadly recruited to promoters
Authors: Soffers Jelly H.M. , Alcantara Sergio Garcia-Moreno , Li Xuanying , Shao Wanqing , Seidel Christopher W. , Li Hua , Zeitlinger Julia , Abmayr Susan M. , Workman Jerry L. 
Published: June 2021

AbstractThe Spt/Ada-Gcn5 Acetyltransferase (SAGA) coactivator complex has multiple modules with different enzymatic and non-enzymatic functions. How each module contributes to gene activation in specific biological contexts is not well understood. Here we analyzed the role of the non-enzymatic core module duringDrosophilaoogenesis. We show that depletion of several SAGA-specific subunits belonging to the core module blocked egg chamber development during mid-oogenesis stages, resulting in stronger phenotypes than those obtained after depletion of SAGA’s histone acetyltransferase module or deubiquitination module. These results, as well as additional genetic analyses pointing to an interaction with TBP, suggested a differential role of SAGA modules at different promoter types. However, SAGA subunits co-occupied all promoter types of active genes in ChIP-seq and ChIP-nexus experiments. Thus, the SAGA complex appears to occupy promoters in its entirety, consistent with the strong biochemical integrity of the complex. The high-resolution genomic binding profiles are congruent with SAGA recruitment by activators upstream of the start site, and retention on chromatin by interactions with modified histones downstream of the start site. The stronger genetic requirement of the core module during oogenesis may therefore be explained through its interaction with TBP or its role in recruiting the enzymatic modules to the promoter. We propose the handyman principle, which posits that a distinct genetic requirement for specific components may conceal the fact that the entire complex is physically present.Author SummaryEmbryonic development critically relies on the differential expression of genes in different tissues. This involves the dynamic interplay between DNA, sequence-specific transcription factors, coactivators and chromatin remodelers which guide the transcription machinery to the appropriate promoters for productive transcription. To understand how this happens at the molecular level, we need to understand when and how coactivator complexes such as SAGA function. SAGA consists of multiple modules with well characterized enzymatic functions. This study shows that the non-enzymatic core module of SAGA is required forDrosophilaoogenesis, while the enzymatic functions are largely dispensable. Despite this differential requirement, SAGA subunits appear to be broadly recruited to all promoter types, consistent with the biochemical integrity of the complex. These results suggest that genetic requirements and physical organization do not always go hand in hand.