bluuebunny/crossref_metadata_2025_split huggingface dataset:
Wastewater-Based Epidemiological Modeling for Continuous Surveillance of COVID-19 Outbreak
Authors: Fazli Mehrdad , Sklar Samuel , Porter Michael D. , French Brent A. , Shakeri Heman 
Published: October 2021

AbstractUsing wastewater surveillance as a continuous pooled sampling technique has been in place in many countries since the early stages of the outbreak of COVID-19. Since the beginning of the outbreak, many research works have emerged, studying different aspects of viral SARS-CoV-2 DNA concentrations (viral load) in wastewater and its potential as an early warning method. However, one of the questions that has remained unanswered is the quantitative relation between viral load and clinical indicators such as daily cases, deaths, and hospitalizations. Few studies have tried to couple viral load data with an epidemiological model to relate the number of infections in the community to the viral burden. This paper proposes a stochastic wastewater-based SEIR model to showcase the importance of viral load in the early detection and prediction of an outbreak in a community. We built three models based on whether or not they use the case count and viral load data and compared their simulations and forecasting quality. Our results demonstrate that a simple SEIR model based on viral load data can reliably predict the number of infections in the future. Therefore, wastewater-based surveillance is a promising way of monitoring the spread of COVID-19 and can provide city officials with timely information about the circulation of COVID-19 in the community.
Single cell transcriptomics reveals distinct effector profiles of infiltrating T cells in lupus skin and kidney
Authors: Dunlap Garrett S. , Billi Allison C. , Ma Feiyang , Maz Mitra P. , Tsoi Lam C. , Wasikowski Rachael , Gudjonsson Johann E. , Kahlenberg J. Michelle , Rao Deepak A. 
Published: October 2021

AbstractCutaneous lupus is commonly present in patients with systemic lupus erythematosus (SLE) but can also exist as an isolated manifestation without further systemic involvement. T cells have been strongly suspected to contribute to the pathology of cutaneous lupus, yet our understanding of the T cell phenotypes and functions in the skin in lupus remains incomplete, and the extent to which lupus T cell infiltrates in skin resemble those in other tissue beds is unknown. Here, we present a detailed single-cell RNA sequencing profile of T and NK cell populations present within lesional and non-lesional skin biopsies of patients with cutaneous lupus. We identified multiple lymphocyte clusters, including both CD4 and CD8 T cells, NK cells, regulatory T cells, and a population of strongly interferon-responding cells that was present in patients with cutaneous lupus but absent in healthy donors. T cells across clusters from both lesional and non-lesional skin biopsies expressed elevated levels of interferon simulated genes (ISGs); however, compared to T cells from control skin, T cells from cutaneous lupus lesions did not show elevated expression profiles of activation, cytotoxicity, or exhaustion. Integrated analyses comparing skin T/NK cells to lupus nephritis kidney T/NK cells indicated that skin lymphocytes appeared less activated and lacked the expanded cytotoxic populations prominent in lupus nephritis. An integrated comparison of skin T cells from lupus and systemic sclerosis revealed similar activation profiles but an elevated ISG signature specific to cells from lupus skin biopsies. Overall, these data represent the first detailed transcriptomic analysis of the of T and NK cells in cutaneous lupus at the single cell level and have enabled a cross-tissue comparison that highlighted the stark differences in composition and activation of T/NK cells in distinct tissues in lupus.
Machine Learning Prediction of Non-Coding Variant Impact in Human Retinal Cis-Regulatory Elements
Authors: VandenBosch Leah S. , Luu Kelsey , Timms Andrew E. , Challam Shriya , Wu Yue , Lee Aaron Y. , Cherry Timothy J. 
Published: October 2021

AbstractPurposePrior studies demonstrate the significance of specific cis-regulatory variants in retinal disease, however determining the functional impact of regulatory variants remains a major challenge. In this study, we utilize a machine learning approach, trained on epigenomic data from the adult human retina, to systematically quantify the predicted impact of cis-regulatory variants.MethodsWe used human retinal DNA accessibility data (ATAC-seq) to determine a set of 18.9k high-confidence putative cis-regulatory elements. 80% of these elements were used to train a machine learning model utilizing a gapped k-mer support vector machine-based approach. In silico saturation mutagenesis and variant scoring was applied to predict the functional impact of all potential single nucleotide variants within cis-regulatory elements. Impact scores were tested in a 20% hold-out dataset and compared to allele population frequency, phylogenetic conservation, transcription factor (TF) binding motifs, and existing massively parallel reporter assay (MPRA) data.ResultsWe generated a model that distinguishes between human retinal regulatory elements and negative test sequences with 95% accuracy. Among a hold-out test set of 3.7k human retinal CREs, all possible single nucleotide variants (SNVs) were scored. Variants with negative impact scores correlated with reduced population allele frequency, higher phylogenetic conservation of the reference allele, disruption of predicted TF binding motifs, and massively-parallel reporter expression.ConclusionsWe demonstrated the utility of human retinal epigenomic data to train a machine learning model for the purpose of predicting the impact of non-coding regulatory sequence variants. Our model accurately scored sequences and predicted putative transcription factor binding motifs. This approach has the potential to expedite the characterization of pathogenic non-coding sequence variants in the context of unexplained retinal disease.
Chikungunya virus vaccine candidate incorporating synergistic mutations is attenuated and protects against virulent virus challenge
Authors: Lentscher Anthony J. , McAllister Nicole , Griswold Kira A. , Martin James L. , Welsh Olivia L. , Sutherland Danica M. , Silva Laurie A. , Dermody Terence S. 
Published: October 2021

ABSTRACTBackgroundChikungunya virus (CHIKV) is an arbovirus that periodically reemerges to cause large epidemics of arthritic disease. While the robust immunity elicited by live-attenuated virus (LAV) vaccine candidates makes them attractive, CHIKV vaccine development has been hampered by a high threshold for acceptable adverse events.MethodsWe evaluated the vaccine potential of a recently described LAV, SKE, that exhibits diminished replication in skeletal muscle cells due to insertion of target sequences for skeletal muscle-specific miR-206. We also evaluated whether these target sequences could augment safety of a LAV encoding a previously described attenuating mutation, E2 G82R, which on its own was too reactogenic in clinical trials. Attenuation of viruses containing these mutations was compared with a double mutant, SKE G82R.ResultsSKE was attenuated in both immunodeficient and immunocompetent mice and induced a robust neutralizing antibody response, indicating its vaccine potential. However, only SKE G82R elicited diminished swelling in immunocompetent mice at early time points post-inoculation, indicating that these mutations synergistically enhance safety of the vaccine candidate.ConclusionsThese data suggest that restriction of LAV replication in skeletal muscle enhances tolerability of reactogenic vaccine candidates and may improve the rational design of CHIKV vaccines.
Structural identification of individual helical amyloid filaments by integration of cryo-electron microscopy-derived maps in comparative morphometric atomic force microscopy image analysis
Authors: Lutter Liisa , Al-Hilaly Youssra K. , Serpell Christopher J. , Tuite Mick F. , Wischik Claude M. , Serpell Louise C. , Xue Wei-Feng 
Published: October 2021

ABSTRACTThe presence of amyloid fibrils is a hallmark of more than 50 human disorders, including neurodegenerative diseases and systemic amyloidoses. A key unresolved challenge in understanding the involvement of amyloid in disease is to explain the relationship between individual structural polymorphs of amyloid fibrils, in potentially mixed populations, and the specific pathologies with which they are associated. Although cryo-electron microscopy (cryo-EM) and solid-state nuclear magnetic resonance (ssNMR) spectroscopy methods have been successfully employed in recent years to determine the structures of amyloid fibrils with high resolution detail, they rely on ensemble averaging of fibril structures in the entire sample or significant subpopulations. Here, we report a method for structural identification of individual fibril structures imaged by atomic force microscopy (AFM) by integration of high-resolution maps of amyloid fibrils determined by cryo-EM in comparative AFM image analysis. This approach was demonstrated using the hitherto structurally unresolved amyloid fibrils formed in vitro from a fragment of tau (297-391), termed ‘dGAE’. Our approach established unequivocally that dGAE amyloid fibrils bear no structural relationship to heparin-induced tau fibrils formed in vitro. Furthermore, our comparative analysis resulted in the prediction that dGAE fibrils are closely related structurally to the paired helical filaments (PHFs) isolated from Alzheimer’s disease (AD) brain tissue characterised by cryo-EM. These results show the utility of individual particle structural analysis using AFM, provide a workflow of how cryo-EM data can be incorporated into AFM image analysis and facilitate an integrated structural analysis of amyloid polymorphism.
In an arms race between host and parasite, a lungworm’s ability to infect a toad is determined by host susceptibility, not parasite preference
Authors: Eyck Harrison JF. , Brown Gregory P. , Rollins Lee A. , Shine Richard 
Published: October 2021

AbstractEvolutionary arms races can alter both parasite infectivity and host resistance, and it is difficult to separate the effects of these twin determinants of infection outcomes. Using a co-introduced, invasive host-parasite system (the lungworm Rhabdias pseudosphaerocephala and the cane toad Rhinella marina), we quantified behavioural responses of parasite larvae to skin-chemical cues of toads from different invasive populations, and rates at which hosts became infected following standardised exposure to lungworms. Chemical cues from toad skin altered host-seeking behaviour by parasites, similarly among populations. The number of infection attempts (parasite larvae entering the host’s body) also did not differ between populations, but rates of successful infection (establishment of adult worm in host lungs) was higher for range-edge toads than for range-core conspecifics. Thus, lower resistance to parasite infection in range-edge toads appears to be due to less effective immune defences of the host rather than differential behavioural responses of the parasite. In this ongoing host-parasite arms-race, changing outcomes appear to be driven by shifts in host immunocompetence.
CandyCollect: At-home saliva sampling for capture of respiratory pathogens
Authors: Lee Ulri N. , Su Xiaojing , Hieber Damielle L. , Tu Wan-chen , McManamen Anika M. , Takezawa Meg G. , Hassan Grant W. , Chan Tung Ching , Adams Karen N. , Wald Ellen R. , DeMuri Gregory P. , Berthier Erwin , Theberge Ashleigh B. , Thongpang Sanitta 
Published: October 2021

AbstractStreptococcus pyogenes is a major human-specific bacterial pathogen and a common cause of a wide range of symptoms from mild infection such as pharyngitis (commonly called strep throat) to life-threatening invasive infection and post-infectious sequelae. Traditional methods for diagnosis include collecting a sample using a pharyngeal swab, which can cause discomfort and even discourage adults and children from seeking proper testing and treatment in the clinic. Saliva samples are an alternative to pharyngeal swabs. To improve the testing experience for strep throat, we developed a novel lollipop-inspired sampling platform (called CandyCollect) to capture bacteria in saliva. The device can be used in clinics or in the home and shipped back to a lab for analysis, integrating with telemedicine. CandyCollect is designed to capture bacteria on an oxygen plasma treated polystyrene surface embedded with flavoring substances to enhance the experience for children and inform the required time to complete the sampling process. In addition, the open channel structure prevents the tongue from scraping and removing the captured bacteria. Flavoring substances did not affect bacterial capture and the device has a shelf life of at least 2 months (with experiments ongoing to extend the shelf life). We performed a usability study with 17 participants who provided feedback on the device design and the dissolving time of the candy. This technology and advanced processing techniques, including polymerase chain reaction (PCR), will enable user-friendly and effective diagnosis of streptococcal pharyngitis.
Tuning the Pennes Perfusion Rate to Model Large Vessel Cooling Effects in Hepatic Radiofrequency Ablation
Authors: Vaidya Nikhil , Baragona Marco , Lavezzo Valentina , Maessen Ralph , Veroy Karen 
Published: October 2021

AbstractRadio-frequency ablation (RFA) has become a popular method for the minimally invasive treatment of liver cancer. However, the success rate of these treatments depends heavily on the amount of experience the clinician possesses. Mathematical modelling can help mitigate this problem by providing an indication of the treatment outcome. Thermal lesions in RFA are affected by the cooling effect of both fine-scale and large-scale blood vessels. The exact model for large-scale blood vessels is advection-diffusion, i.e. a model capable of producing directional effects, which are known to occur in certain cases. In previous research, in situations where directional effects do not occur, the advection term in the blood vessel model has been typically replaced with the Pennes perfusion term, albeit with a higher-than usual perfusion rate. Whether these values of the perfusion rate appearing in literature are optimal for the particular vessel radii in question, has not been investigated so far. The present work aims to address this issue. An attempt has been made to determine, for values of vessel radius between 0.55 mm and 5 mm, best estimates for the perfusion rate which minimize the error in thermal lesion volumes between the perfusion-based model and the advection-based model. The results for the best estimate of the perfusion rate presented may be used in existing methods for fast estimation of RFA outcomes. Furthermore, the possible improvements to the presented methodology have been highlighted.
Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brain
Authors: Yang Yang , Arseni Diana , Zhang Wenjuan , Huang Melissa , Lövestam Sofia , Schweighauser Manuel , Kotecha Abhay , Murzin Alexey G. , Peak-Chew Sew Y. , Macdonald Jennifer , Lavenir Isabelle , Garringer Holly J. , Gelpi Ellen , Newell Kathy L. , Kovacs Gabor G. , Vidal Ruben , Ghetti Bernardino , Falcon Benjamin , Scheres Sjors H.W. , Goedert Michel 
Published: October 2021

AbstractFilament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. We report the cryo-EM structures of Aβ42 filaments from brain. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease and Type II filaments in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, Aβ42 deposits were made of Type II filaments. Knowledge of Aβ42 filament structures from human brain may lead to the development of inhibitors of assembly and improved imaging agents.
Fetal neural progenitors process TLR signals from bacterial components to enhance proliferation and rework brain development
Authors: Mann Beth , Crawford Jeremy Chase , Reddy Kavya , Lott Josi , Youn Yong Ha , Gao Geli , Guy Cliff , Chou Ching-Heng , Darnell Daniel , Trivedi Sanchit , Bomme Perrine , Loughran Allister J. , Thomas Paul G. , Han Young-Goo , Tuomanen Elaine I. 
Published: October 2021

SummaryBacterial cell wall, a universal pathogen-associated molecular pattern (PAMP), crosses the placenta into the fetal brain. We determined that PAMPs interact with TLR2/6 on murine fetal neural progenitor cells (NPCs) to induce overexpansion of all neocortical layers leading to a larger, folded cortex and abnormal postnatal behavior. The NPC overexpansion originated at E10 and targeted ventricular radial glia (vRG), the primary NPC, by shortening cell cycle and increasing self-renewal. The mechanism involved two novel signaling pathways in NPCs mediated by recognition of bacterial PAMPs by TLR2/6 including: a) loss of primary cilia, activation of hedgehog signaling, and increased FOXG1 and b) increased PI3K/AKT activity. These findings reveal PAMP/TLR2/6 acts as a morphogen in fetal neurodevelopment. In addition, the loss ofTlr2orTlr6without pathogenic challenge, increased the number of neurons, establishing the requirement for an endogenous TLR2 signal for normal neurodevelopment in the embryo.
Valuation of carbon services produced by wild animals finances conservation
Authors: Berzaghi Fabio , Chami Ralph , Cosimano Thomas , Fullenkamp Connel 
Published: October 2021

AbstractFilling the global biodiversity financing gap will require significant investments from financial markets, which demand credible valuations of ecosystem services and natural capital. However, current valuation approaches discourage investment in conservation because their results cannot be verified using market-determined prices. Here, we bridge the gap between finance and conservation by valuing only wild animals’ carbon services for which market prices exist. By projecting the future path of carbon service production using a spatially-explicit demographic model, we place a credible value on the carbon-capture services produced by African forest elephants. If elephants were protected, their services would be worth $35.9 billion (24.3-41.2) and store 377 MtC (318-388) across tropical Africa. Our methodology can also place lower bounds on the social cost of nature degradation. Poaching would result in $10-14 billion of lost carbon services. Our methodology enables the integration of animal services into global financial markets with major implications for conservation, local socio-economies, and conservation.
Specificities and commonalities of carbapenemase producing Escherichia coli isolated in France from 2012 to 2015
Authors: Patiño-Navarrete Rafael , Rosinski-Chupin Isabelle , Cabanel Nicolas , Dieudonné Zongo Pengdbamba , Héry Mélanie , Oueslati Saoussen , Girlich Delphine , Dortet Laurent , Bonnin Rémy A , Naas Thierry , Glaser Philippe 
Published: October 2021

ABSTRACTCarbapenemase-producing Escherichia coli (CP-Ec) represent a major public health threat with a risk of dissemination in the community as it has occurred for lineages producing extended spectrum ß-lactamases. To characterize the extend of CP-Ec spread in France, isolates from screening and infection samples received at the French National Reference Centre laboratory (F-NRC) for carbapenemase-producing Enterobacterales were investigated. Six hundred and ninety one CP-Ec isolates collected between 2012 and 2015 and 22 before were fully sequenced. Analysis of their genome sequences revealed some disseminating multidrug resistant (MDR) lineages frequently acquiring diverse carbapenemase genes mainly belonging to clonal complex (CC) 23 (ST 410) and CC10 (ST10, ST167) and sporadic isolates including rare ST131 isolates (n=17). However, the most represented ST was ST38 (n=92) with four disseminated lineages carrying blaOXA-48-like genes inserted in the chromosome. Globally, the most frequent carbapenemase gene (n=457) was blaOXA-48. It was also less frequently associated with MDR isolates being the only resistance gene in 119 isolates. Thus, outside the ST38 clades, its acquisition was frequently sporadic with no sign of dissemination, reflecting the circulation of the IncL plasmid pOXA-48 in France and its high frequency of conjugation. In contrast blaOXA-181 or blaNDM genes were often associated with the evolution of MDR E. coli lineages characterized by mutations in ftsI and ompC.IMPORTANCECarbapenemase-producing Escherichia coli (CP-Ec) might be difficult to detect, as minimal inhibitory concentrations can be very low. However, their absolute number and their proportion among carbapenem-resistant Enterobacterales have been increasing, as reported by WHO and national surveillance programs. This suggests a still largely uncharacterized community spread of these isolates. Here we have characterized the diversity and evolution of CP-Ec isolated in France before 2016. We show that carbapenemase genes are associated with a wide variety of E. coli genomic backgrounds and a small number of dominant phylogenetic lineages. In a significant proportion of CP-Ec, the most frequent carbapenemase gene blaOXA-48, was detected in isolates lacking any other resistance gene, reflecting the dissemination of pOXA-48 plasmids, likely in the absence of any antibiotic pressure. In contrast carbapenemase gene transfer may also occur in multi-drug resistant E. coli, ultimately giving rise to at-risk lineages encoding carbapenemases with a high potential of dissemination.