bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of sparse biclustering algorithms for gene expression datasets
Authors: Nicholls Kath , Wallace Chris
Published: December 2020

Gene clustering and sample clustering are commonly used to find patterns in gene expression datasets. However, in heterogeneous samples (e.g. different tissues or disease states), genes may cluster differently. Biclustering algorithms aim to solve this issue by performing sample clustering and gene clustering simultaneously. Existing reviews of biclustering algorithms have yet to include a number of more recent algorithms and have based comparisons on simplistic simulated datasets without specific evaluation of biclusters in real datasets, using less robust metrics.

In this study we compared four classes of sparse biclustering algorithms on a range of simulated and real datasets. In particular we use a knockout mouse RNA-seq dataset to evaluate each algorithm’s ability to simultaneously cluster genes and cluster samples across multiple tissues. We found that Bayesian algorithms with strict sparsity constraints had high accuracy on the simulated datasets and didn’t require any post-processing, but were considerably slower than other algorithm classes. We assessed whether non-negative matrix factorisation algorithms can be repurposed for biclustering and found that, although the raw output was poor, after using a sparsity-inducing post-processing procedure we introduce, one such algorithm was one of the most highly ranked on real datasets. We also exhibit the limitations of biclustering algorithms by varying the complexity of simulated datasets. The algorithms generally struggled on simulated datasets with a large number of implanted factors, or with a large number of genes. In real datasets, the algorithms rarely returned clusters containing samples from multiple tissues, which highlights the need for further thought in the design and analysis of multi-tissue studies to avoid differences between tissues dominating the analysis.

Code to run the analysis is available athttps://github.com/nichollskc/biclust_comp, including wrappers for each algorithm, implementations of evaluation metrics, and code to simulate datasets and perform pre- and post-processing. The full tables of results are available athttps://doi.org/10.5281/zenodo.4317556
Activity Budget and Postural Behaviours in Orangutans on Bukit Merah Orang Utan Island for Assessing Captive Great Ape Welfare
Authors: Kamaluddin Siti Norsyuhada , Matsuda Ikki , Md-Zain Badrul Munir
Published: December 2020

Assessments of the welfare status of captive and semi-captive animals often compare how their expression of natural behaviours differs from that of free-ranging conspecifics. Bukit Merah Orang Utan Island (BMOUI) is the only orangutan rehabilitation and conservation centre in the Malay Peninsula. We recorded and analyzed the activity budget and postural behaviours of orangutans moving freely in the enclosures on BMOUI to evaluate their welfare status. From December 2015 to December 2016, we observed three individuals: an adult male, an adult female and a subadult male, and collected 252 hours of focal data (84 hr/individual). The orangutans’ activity budget was dominated by resting (60%), feeding (13%), playing (14%) and moving (9%). The study individuals heavily relied on the artificial foods (79.2%), and they spent majority of their time on the ground (85.1%) with occasional arboreal observations like using the wooden tree platform or a rope. Despite some significant individual differences, behavioural categories followed a similar trend: resting > feeding > moving > playing, except that the subadult male spent significantly more time playing (35%) than the two adults (3–4%). The most predominant posture was sitting (47.0%), followed by pronograde standing (29.4%), lying (10.5%) and clinging (4.5%). Our results suggest that orangutans on BMOUI engage in less feeding but more resting, and show less postural diversity, than free-ranging individuals. We propose that appropriate interventions to shift activity budgets, especially feeding vs. resting, and postural behaviours of captive orangutans towards those found in free-ranging orangutans might be beneficial for their welfare and survival; however, the conclusions we can draw are limited due to the small sample size, and thus until the captive behaviours of a larger number of orang-utans has been described, these results must be considered preliminary and just a case study.
The rapid, massive growth of COVID-19 authors in the scientific literature
Authors: Ioannidis John P.A. , Salholz-Hillel Maia , Boyack Kevin W. , Baas Jeroen
Published: December 2020

We examined the extent to which the scientific workforce in different fields was engaged in publishing COVID-19-related papers. According to Scopus (data cut, August 1, 2021), 210,183 COVID-19-related publications included 720,801 unique authors, of which 360,005 authors had published at least 5 full papers in their career and 23,520 authors were at the top 2% of their scientific subfield based on a career-long composite citation indicator. The growth of COVID-19 authors was far more rapid and massive compared with cohorts of authors historically publishing on H1N1, Zika, Ebola, HIV/AIDS and tuberculosis. All 174 scientific subfields had some specialists who had published on COVID-19. In 109 of the 174 subfields of science, at least one in ten active, influential (top-2% composite citation indicator) authors in the subfield had authored something on COVID-19. 52 hyper-prolific authors had already at least 60 (and up to 227) COVID-19 publications each. Among the 300 authors with the highest composite citation indicator for their COVID-19 publications, most common countries were USA (n=67), China (n=52), UK (n=32), and Italy (n=18). The rapid and massive involvement of the scientific workforce in COVID-19-related work is unprecedented and creates opportunities and challenges. There is evidence for hyper-prolific productivity.
The role of anatomical connection strength for interareal communication in macaque cortex
Authors: Vezoli Julien , Vinck Martin , Bosman Conrado Arturo , Bastos André Moraes , Lewis Christopher Murphy , Kennedy Henry , Fries Pascal
Published: December 2020

What is the relationship between anatomical connection strength and rhythmic synchronization? Simultaneous recordings of 15 cortical areas in two macaque monkeys show that interareal networks are functionally organized in spatially distinct modules with specific synchronization frequencies, i.e. frequency-specific functional connectomes. We relate the functional interactions between 91 area pairs to their anatomical connection strength defined in a separate cohort of twenty six subjects. This reveals that anatomical connection strength predicts rhythmic synchronization and vice-versa, in a manner that is specific for frequency bands and for the feedforward versus feedback direction, even if interareal distances are taken into account. These results further our understanding of structure-function relationships in large-scale networks covering different modality-specific brain regions and provide strong constraints on mechanistic models of brain function. Because this approach can be adapted to non-invasive techniques, it promises to open new perspectives on the functional organization of the human brain.
A low-autofluorescence, transparent resin for multiphoton 3D printing
Authors: Flamourakis George , Kordas Antonis , Barmparis Georgios D. , Ranella Anthi , Farsari Maria
Published: December 2020

Multiphoton lithography allows the high resolution, free-form 3D printing of structures such as micro-optical elements and 3D scaffolds for Tissue Engineering. A major obstacle in its application in these fields is material and structure autofluorescence. Existing photoresists promise near zero fluorescent in expense of poor mechanical properties, and low printing efficiency. Sudan Black B is a molecular quencher used as a dye for biological studies and as means of decreasing the autofluorescence of polymers. In our study we report the use of Sudan Black B as both a photoinitiator and as a post-fabrication treatment step, using the zirconium silicate SZ2080™ for the development of a non-fluorescent composite. We use this material for the 3D printing of micro-optical elements, and meso-scale scaffolds for Mesenchymal Stem Cell cultures. Our results show the hybrid, made photosensitive with Sudan Black B, can be used for the fabrication of high resolution, highly transparent, autofluorescence-free microstructures.
Choice of assemblers has a critical impact on de novo assembly of SARS-CoV-2 genome and characterizing variants
Authors: Islam Rashedul , Raju Rajan Saha , Tasnim Nazia , Shihab Md. Istiak Hossain , Bhuiyan Maruf Ahmed , Araf Yusha , Islam Tofazzal
Published: December 2020

Background

Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic following its initial emergence in China. Using next-generation sequencing technologies, a large number of SARS-CoV-2 genomes are being sequenced at an unprecedented rate and being deposited in public repositories. For the de novo assembly of the SARS-CoV-2 genomes, a myriad of assemblers is being used, although their impact on the assembly quality has not been characterized for this virus. In this study, we aim to understand the variabilities on assembly qualities due to the choice of the assemblers.

Results

We performed 6,648de novoassemblies of 416 SARS-CoV-2 samples using 8 different assemblers with different k-mers. We used Illumina paired-end sequencing reads and compared the genome assembly quality to that of different assemblers. We showed the choice of assemblers plays a significant role in reconstructing the SARS-CoV-2 genome. Two metagenomic assemblers e.g. MEGAHIT and metaSPAdes performed better compared to others in most of the assembly quality metrics including, recovery of a larger fraction of the genome, constructing larger contigs and higher N50, NA50 values etc. We showed that at least 09% (259/2,873) of the variants present in the assemblies between MEGAHIT and metaSPAdes are unique to the assembly methods.

Conclusion

Our analyses indicate the critical role of assembly methods for assembling SARS-CoV-2 genome using short reads and their impact on variant characterization. This study could help guide future studies to determine which assembler is best suited for the de novo assembly of virus genomes.
Python Interfaces for the Smoldyn Simulator
Authors: Singh Dilawar , Andrews Steven S.
Published: December 2020

Motivation

Smoldyn is a particle-based biochemical simulator that is frequently used for systems biology and biophysics research. Previously, users could only define models using text-based input or a C/C++applicaton programming interface (API), which were convenient, but limited extensibility.

Results

We added a Python API to Smoldyn to improve integration with other software tools such as Jupyter notebooks, other Python code libraries, and other simulators. It includes low-level functions that closely mimic the existing C/C++API and higher-level functions that are more convenient to use. These latter functions follow modern object-oriented Python conventions.

Availability

Smoldyn is open source and free, available athttp://www.smoldyn.org, and can be installed with the Python package managerpip. It runs on Mac, Windows, and Linux.

Contact

steven.s.andrews@gmail.com

Supplementary information

Documentation is available athttp://www.smoldyn.org/SmoldynManual.pdfandhttps://smoldyn.readthedocs.io/en/latest/python/api.html.
Putative Pseudolysogeny-Dependent Phage Gene Implicated in the Superinfection Resistance ofCutibacterium acnes
Authors: Wottrich Stephanie , Mendonca Stacee , Safarpour Cameron , Nguyen Christine , Marinelli Laura J. , Modlin Robert L. , Parker Jordan Moberg
Published: December 2020

Background

Bacteriophage therapy is a promising option to minimize the risk of treatment-associated antibiotic resistance inCutibacterium acnes. A novel phage (Aquarius) was isolated and analyzed to explore characteristics ofC. acnesphages that may confer lysis-evasion properties.

Materials and Methods

Phage superinfection resistance assays were performed with a range ofC. acnesphages, which were assayed for pseudolysogeny via phage release assays and episome PCR. Bioinformatics and qRT-PCR were used to identify candidate genes related to observed phenotypes.

Results

Assay findings indicated that infectedC. acnesstrains were broadly resistant to superinfection and were capable of forming stable pseudolysogens. A conserved Ltp family-like gene contained protein signatures which may be contributing to phage-mediated superinfection resistance in a pseudolysogeny-dependent manner.

Conclusions

C. acnesbacteria are capable of harboring phage pseudolysogens, and this phenomenon may result in superinfection resistance, necessitating consideration in targeting optimization ofC. acnesphage-based therapy.
Identification of inhibitors of SARS-CoV-2 3CL-Pro enzymatic activity using a small molecule in-vitro repurposing screen
Authors: Kuzikov Maria , Costanzi Elisa , Reinshagen Jeanette , Esposito Francesca , Vangeel Laura , Wolf Markus , Ellinger Bernhard , Claussen Carsten , Geisslinger Gerd , Corona Angela , Iaconis Daniela , Talarico Carmine , Manelfi Candida , Cannalire Rolando , Rossetti Giulia , Gossen Jonas , Albani Simone , Musiani Francesco , Herzog Katja , Ye Yang , Giabbai Barbara , Demitri Nicola , Jochmans Dirk , De Jonghe Steven , Rymenants Jasper , Summa Vincenzo , Tramontano Enzo , Beccari Andrea R. , Leyssen Pieter , Storici Paola , Neyts Johan , Gribbon Philip , Zaliani Andrea
Published: December 2020

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, and have identified 62 additional compounds with IC50 values below 1 μM and profiled their selectivity towards Chymotrypsin and 3CL-Pro from the MERS virus. A subset of 8 inhibitors showed anti-cytopathic effect in a Vero-E6 cell line and the compounds thioguanosine and MG-132 were analysed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

Graphical abstract

Abstract Figure.

Workflow for identification and profiling of inhibitors of SARS-CoV-2 3CL-Pro using a large scale repurposing and bioactive compound collection (rhs). Primary assay principle based on quenched FRET peptide substrate of SARS-CoV-2 3CL-Pro (lhs). Inhibiting compounds reduce fluorescence signal relative to DMSO controls. Hit profiling using X-ray.
Sex-specific body mass ageing trajectories in adult Asian elephants
Authors: Lalande Lucas D. , Lummaa Virpi , Aung Htoo H. , Htut Win , Nyein U. Kyaw , Berger Vérane , Briga Michael
Published: December 2020

In species with marked sexual dimorphism and where one sex undergoes stronger intrasexual competition, that sex is expected to age earlier or quicker. Here, we utilise a unique, longitudinal dataset of a semi-captive population of Asian elephants (Elephas maximus), a species with marked male-biased intrasexual competition, with males being larger and living shorter, and test the hypothesis that males show earlier and/or faster body mass ageing than females. We show sex-specific body mass ageing trajectories: adult males gained weight up to the age of 48 years old, followed by a decrease in body mass until natural death. In contrast, adult females gained body mass with age until a body mass decline in the last year of life. Our study shows that sex-specific life-histories shape ageing patterns, consistent with the predictions of the classical theory of ageing.
Shape Morphing Technique Can Accurately Predict Pelvic Bone Landmarks
Authors: Kuchař Michal , Henyš Petr , Rejtar Pavel , Hájek Petr
Published: December 2020

Diffeomorphic shape registration allows for the seamless geometric alignment of shapes. In this study, we demonstrated the use of a registration algorithm to automatically seed anthropological landmarks on the CT images of the pelvis. We found a high correlation between manually and automatically seeded landmarks. The registration algorithm makes it possible to achieve a high degree of automation with the potential to reduce operator errors in the seeding of anthropological landmarks. The results of this study represent a promising step forward in effectively defining the anthropological measures of the human skeleton.

Highlights

The clinical CT scan is a feasible alternative to skeletal collections and body donor programs.

Pelvic morphology is complex, sexually dimorphic and is proven to being a good demonstration model for the performance analysis of registration algorithm for automatic landmark seeding.

The landmark seeding using registration algorithm can save time and effort in anthropological analysis.
Motor planning brings human primary somatosensory cortex into action-specific preparatory states
Authors: Ariani Giacomo , Pruszynski J. Andrew , Diedrichsen Jörn
Published: December 2020

Motor planning plays a critical role in producing fast and accurate movement. Yet, the neural processes that occur in human primary motor and somatosensory cortex during planning, and how they relate to those during movement execution, remain poorly understood. Here we used 7T functional magnetic resonance imaging (fMRI) and a delayed movement paradigm to study single finger movement planning and execution. The inclusion of no-go trials and variable delays allowed us to separate what are typically overlapping planning and execution brain responses. Although our univariate results show widespread deactivation during finger planning, multivariate pattern analysis revealed finger-specific activity patterns in contralateral primary somatosensory cortex (S1), which predicted the planned finger action. Surprisingly, these activity patterns were as informative as those found in contralateral primary motor cortex (M1). Control analyses ruled out the possibility that the detected information was an artifact of subthreshold movements during the preparatory delay. Furthermore, we observed that finger-specific activity patterns during planning were highly correlated to those during execution. These findings reveal that motor planning activates the specific S1 and M1 circuits that are engaged during the execution of a finger press, while activity in both regions is overall suppressed. We propose that preparatory states in S1 may improve movement control through changes in sensory processing or via direct influence of spinal motor neurons.

Significance statement

Motor planning is important for good behavioral performance, yet it is unclear which neural processes underlie the preparation of the nervous system for an upcoming movement. Using high-resolution functional neuroimaging, we investigated how motor planning for finger presses changes the activity state in primary motor and primary somatosensory cortex, and how brain responses during planning and execution relate to each other. We show that planning leads to finger-specific activation in both M1 and S1, which is highly similar to the finger-specific activity patterns elicited during execution. Our findings suggest that S1 is being specifically prepared for an upcoming action, either to actively contribute to the outflowing motor command or to enable action-specific sensory gating.
Modeling effectiveness of testing strategies to prevent COVID-19 in nursing homes —United States, 2020
Authors: See Isaac , Paul Prabasaj , Slayton Rachel B. , Steele Molly K. , Stuckey Matthew J. , Duca Lindsey , Srinivasan Arjun , Stone Nimalie , Jernigan John A. , Reddy Sujan C.
Published: December 2020

Background

SARS-CoV-2 outbreaks in nursing homes can be large with high case fatality. Identifying asymptomatic individuals early through serial testing is recommended to control COVID-19 in nursing homes, both in response to an outbreak (“outbreak testing” of residents and healthcare personnel) and in facilities without outbreaks (“non-outbreak testing” of healthcare personnel). The effectiveness of outbreak testing and isolation with or without non-outbreak testing was evaluated.

Methods

Using published SARS-CoV-2 transmission parameters, the fraction of SARS-CoV-2 transmissions prevented through serial testing (weekly, every three days, or daily) and isolation of asymptomatic persons compared to symptom-based testing and isolation was evaluated through mathematical modeling using a Reed-Frost model to estimate the percentage of cases prevented (i.e., “effectiveness”) through either outbreak testing alone or outbreak plus non-outbreak testing. The potential effect of simultaneous decreases (by 10%) in the effectiveness of isolating infected individuals when instituting testing strategies was also evaluated.

Results

Modeling suggests that outbreak testing could prevent 54% (weekly testing with 48-hour test turnaround) to 92% (daily testing with immediate results and 50% relative sensitivity) of SARS-CoV-2 infections. Adding non-outbreak testing could prevent up to an additional 8% of SARS-CoV-2 infections (depending on test frequency and turnaround time). However, added benefits of non-outbreak testing were mostly negated if accompanied by decreases in infection control practice.

Conclusions

When combined with high-quality infection control practices, outbreak testing could be an effective approach to preventing COVID-19 in nursing homes, particularly if optimized through increased test frequency and use of tests with rapid turnaround.

Mathematical modeling evaluated the effectiveness of serially testing asymptomatic persons in a nursing home in response to a SARS-CoV-2 outbreak with or without serial testing of asymptomatic staff in the absence of known SARS-CoV-2 infections.
Cell-type specific analysis of physiological action of estrogen in mouse oviducts
Authors: McGlade Emily A. , Herrera Gerardo G. , Stephens Kalli K. , Olsen Sierra L. W. , Winuthayanon Sarayut , Guner Joie , Hewitt Sylvia C. , Korach Kenneth S. , DeMayo Francesco J. , Lydon John P. , Monsivais Diana , Winuthayanon Wipawee
Published: December 2020

One of the endogenous estrogens, 17β-estradiol (E2) is a female steroid hormone secreted from the ovary. It is well established that E2causes biochemical and histological changes in the uterus. The oviduct response to E2is virtually unknown in anin vivoenvironment. In this study, we assessed the effect of E2on each oviductal cell type, using an ovariectomized-hormone-replacement mouse model, single cell RNA-sequencing (scRNA-seq),in situhybridization, and cell-type-specific deletion in mice. We found that each cell type in the oviduct responded to E2distinctively, especially ciliated and secretory epithelial cells. The treatment of exogenous E2did not drastically alter the transcriptomic profile from that of endogenous E2produced during estrus. Moreover, we have identified and validated genes of interest in our datasets that may be used as cell- and region-specific markers in the oviduct. Insulin-like growth factor 1 (Igf1) was characterized as an E2-target gene in the mouse oviduct and was also expressed in human Fallopian tubes. Deletion ofIgf1in progesterone receptor (Pgr)-expressing cells resulted in female subfertility, partially due to an embryo developmental defect and embryo retention within the oviduct. In summary, we have shown that oviductal cell types are differentially regulated by E2and support gene expression changes that are required for normal embryo development and transport in mouse models.
The distribution of onion virulence gene clusters among Pantoea spp
Authors: Stice Shaun P. , Shin Gi Yoon , De Armas Stefanie , Koirala Santosh , Galván Guillermo A. , Siri María Inés , Severns Paul M. , Coutinho Teresa , Dutta Bhabesh , Kvitko Brian H.
Published: December 2020

Pantoea ananatis is a gram-negative bacterium and the primary causal agent of center rot of onions in Georgia. Previous genomic studies identified two virulence gene clusters, HiVir and alt, associated with center rot. The HiVir gene cluster is required to induce necrosis on onion tissues via synthesis of a predicted small molecule toxin. The alt gene cluster aids in tolerance to thiosulfinates generated during onion tissue damage. Whole genome sequencing of other Pantoea species suggest that these gene clusters are present outside of P. ananatis. To assess the distribution of these gene clusters, two PCR primer sets were designed to detect the presence of HiVir and alt. Two hundred fifty-two strains of Pantoea spp. were phenotyped using the red onion scale necrosis (RSN) assay and were assayed using PCR for the presence of these virulence genes. A diverse panel of strains from three distinct culture collections comprised of 24 Pantoea species, 41 isolation sources, and 23 countries, collected from 1946-2019, were tested. There is a significant association between the alt PCR assay and Pantoea strains recovered from symptomatic onion (P<0.001). There is also a significant association of a positive HiVir PCR and RSN assay among P. ananatis strains but not among Pantoea spp., congeners. This may indicate a divergent HiVir cluster or different pathogenicity and virulence mechanisms. Last, we describe natural alt positive [RSN+/HiVir+/alt+] P. ananatis strains, which cause extensive bulb necrosis in a neck-to-bulb infection assay compared to alt negative [RSN+/HiVir+/alt-] P. ananatis strains. A combination of assays that include PCR of virulence genes [HiVir and alt] and an RSN assay can potentially aid in identification of onion-bulb-rotting pathogenic P. ananatis strains.
Spatiotemporal Control of Pathway Sensors and Cross-Pathway Feedback Regulate a Cell Differentiation MAPK Pathway in Yeast
Authors: Prabhakar Aditi , Gonzalez Beatriz , Dionne Heather , Basu Sukanya , Cullen Paul J.
Published: December 2020

Mitogen-Activated Protein Kinase (MAPK) pathways control cell differentiation and the response to stress. MAPK pathways can share components with other pathways yet induce specific responses through mechanisms that remain unclear. InSaccharomyces cerevisiae, the MAPK pathway that controls filamentous growth (fMAPK) shares components with the MAPK pathway that regulates the response to osmotic stress (HOG). By exploring temporal regulation of MAPK signaling, we show here that the two pathways exhibited different patterns of activity throughout the cell cycle. The different patterns resulted from different expression profiles of genes encoding the mucin sensors (MSB2for fMAPK andHKR1for HOG). We also show that positive feedback through the fMAPK pathway stimulated the HOG pathway, presumably to modulate fMAPK pathway activity. By exploring spatial regulation of MAPK signaling, we found that the shared tetraspan protein, Sho1p, which has a dynamic localization pattern, induced the fMAPK pathway at the mother-bud neck. A Sho1p-interacting protein, Hof1p, which also localizes to the mother-bud neck and regulates cytokinesis, also regulated the fMAPK pathway. Therefore, spatial and temporal regulation of pathway sensors, and cross-pathway feedback, regulate a MAPK pathway that controls a cell differentiation response in yeast.
Cross-reactive coronavirus antibodies with diverse epitope specificities and extra-neutralization functions
Authors: Shiakolas Andrea R. , Kramer Kevin J. , Wrapp Daniel , Richardson Simone I. , Schäfer Alexandra , Wall Steven , Wang Nianshuang , Janowska Katarzyna , Pilewski Kelsey A. , Venkat Rohit , Parks Rob , Manamela Nelia P. , Raju Nagarajan , Fechter Emilee Friedman , Holt Clinton M. , Suryadevara Naveenchandra , Chen Rita E. , Martinez David R. , Nargi Rachel S. , Sutton Rachel E. , Ledgerwood Julie E. , Graham Barney S. , Diamond Michael S. , Haynes Barton F. , Acharya Priyamvada , Carnahan Robert H. , Crowe James E. , Baric Ralph S. , Morris Lynn , McLellan Jason S. , Georgiev Ivelin S.
Published: December 2020

The continual emergence of novel coronavirus (CoV) strains, like SARS-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. Coronavirus spike (S) proteins share common structural motifs that could be vulnerable to cross-reactive antibody responses. To study this phenomenon in human coronavirus infection, we applied a high-throughput sequencing method called LIBRA-seq (Linking B cell receptor to antigen specificity through sequencing) to a SARS-CoV-1 convalescent donor sample. We identified and characterized a panel of six monoclonal antibodies that cross-reacted with S proteins from the highly pathogenic SARS-CoV-1 and SARS-CoV-2 and demonstrated a spectrum of reactivity against other coronaviruses. Epitope mapping revealed that these antibodies recognized multiple epitopes on SARS-CoV-2 S, including the receptor binding domain (RBD), N-terminal domain (NTD), and S2 subunit. Functional characterization demonstrated that the antibodies mediated a variety of Fc effector functionsin vitroand mitigated pathological burdenin vivo. The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies that may be useful for preventing potential future coronavirus outbreaks.
Genomic instability is an early event driving chromatin reorganization and escape from oncogene-induced senescence
Authors: Zampetidis C , Galanos P , Angelopoulou A , Zhu Y , Karamitros T , Polyzou A , Mourkioti I , Lagopati N , Mirzazadeh R , Polyzos A , Garnerone S , Gusmao EG , Sofiadis K , Pefani DE , Demaria M , Crosetto N , Maya-Mendoza A , Evangelou K , Bartek J , Papantonis A , Gorgoulis VG
Published: December 2020

Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not timely removed via immune surveillance, senescent cells will also present a detrimental side. Although this has mostly been attributed to the senescence-associated-secretory-phenotype (SASP) of these cells, we recently proposed that “escape” from the senescent state represents another unfavorable outcome. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducibleCDC6oncogene to identify an early-acquired recurrent chromosomal inversion, which harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation uponCDC6induction and for driving cell cycle re-entry and malignant transformation. In summary, we now provide strong evidence in support of genomic instability underlying “escape” from oncogene-induced senescence.

HIGHLIGHTS

Oncogene driven error-prone repair produces early genetic lesions allowing escape from senescence

Cells escaping oncogene-induced senescence display mutational signatures observed in cancer patients

A single recurrent inversion harboring a circadian TF gene suffices for bypassing oncogene-induced senescence

Chromatin loop and compartment remodeling support the “escape” transcriptional program
Mathematical Models for Assessing Vaccination Scenarios in Several Provinces in Indonesia
Authors: Nuraini N. , Khairudin K. , Hadisoemarto P. , Susanto H. , Hasan A. , Sumarti N.
Published: December 2020

To mitigate more casualties from the COVID-19 outbreak, this study assessed optimal vaccination scenarios, considering some existing healthcare conditions and some assumptions, by developing SIQRD (Susceptible-Infected-Quarantine-Recovery-Death) models for Jakarta, West Java, and Banten, in Indonesia. The models included an age-structured dynamic transmission model that naturally could give different treatments among age groups of population. The simulation results show that the timing and period’s length of the vaccination should be well planned and prioritizing particular age groups will give significant impact on the total number of casualties.
Immunological and pathological outcomes of SARS-CoV-2 challenge after formalin-inactivated vaccine immunisation of ferrets and rhesus macaques
Authors: Bewley Kevin R. , Gooch Karen , Thomas Kelly M. , Longet Stephanie , Wiblin Nathan , Hunter Laura , Chan Kin , Brown Phillip , Russell Rebecca A. , Ho Catherine , Slack Gillian , Humphries Holly E. , Alden Leonie , Allen Lauren , Aram Marilyn , Baker Natalie , Brunt Emily , Cobb Rebecca , Fotheringham Susan , Harris Debbie , Kennard Chelsea , Leung Stephanie , Ryan Kathryn , Tolley Howard , Wand Nadina , White Andrew , Sibley Laura , Sarfas Charlotte , Pearson Geoff , Rayner Emma , Xue Xiaochao , Lambe Teresa , Charlton Sue , Gilbert Sarah , Sattentau Quentin J. , Gleeson Fergus , Hall Yper , Funnell Simon , Sharpe Sally , Salguero Francisco J. , Gorringe Andrew , Carroll Miles
Published: December 2020

There is an urgent requirement for safe and effective vaccines to prevent novel coronavirus disease (COVID-19) caused by SARS-CoV-2. A concern for the development of new viral vaccines is the potential to induce vaccine-enhanced disease (VED). This was reported in several preclinical studies with both SARS-CoV-1 and MERS vaccines but has not been reported with SARS-CoV-2 vaccines. We have used ferret and rhesus macaques challenged with SARS-CoV-2 to assess the potential for VED in animals vaccinated with formaldehyde-inactivated SARS-CoV-2 (FIV) formulated with Alhydrogel, compared to a negative control vaccine in ferrets or unvaccinated macaques. We showed no evidence of enhanced disease in ferrets or rhesus macaques given FIV except for mild transient enhanced disease seen at seven days post infection in ferrets. This increased lung pathology was observed early in the infection (day 7) but was resolved by day 15. We also demonstrate that formaldehyde treatment of SARS-CoV-2 reduces exposure of the spike receptor binding domain providing a mechanistic explanation for suboptimal immunity.
Protective effect ofMorus macrouraMiq. fruit extract against acetic acid-induced ulcerative colitis in rats: Involvement of miRNA-223 and TNFα/NFκB/NLRP3 inflammatory pathway
Authors: Salama Rania M. , Darwish Samar F. , Shaffei Ismail El , Elmongy Noura F. , Afifi Manal S. , Abdel-Latif Ghada A.
Published: December 2020

Tumor necrosis factor receptor (TNFR) activation and nuclear factor kappa B (NFκB) expression play a significant role in the activation of nod-like receptor pyrin domain-1 containing 3 (NLRP3) inflammasome inflammatory pathway, which is involved in the pathogenesis of ulcerative colitis (UC). Furthermore, miRNA-223 expression was shown to exert counter-regulatory effect on NLRP3 expression. Interestingly, polyphenols are attaining increased importance for their potential effectiveness in ameliorating certain diseases owing to their antioxidant and anti-inflammatory activity. In accord, our study attempted to investigate the effect of mulberry tree (Morus macroura) fruit extract (MFE) against acetic acid (AA)- induced UC in rats, which is not previously investigated, based on previous promising results for MFE in alleviating gastric ulcer in rats. First, total phenolic (TPC), total flavonoid (TFC), and total anthocyanin content (TAC) were determined in MFE. Then, MFE (300 mg/kg) and sulfasalazine (Sulfa), as a standard treatment (100 mg/kg), were given orally for seven days before intra-rectal induction of UC by AA (2 ml, 4% v/v) on day eight. The extent of UC was evaluated macroscopically and microscopically. Biochemically, the colonic TNFR1, NLRP3, p- NFκB p65, TNFα, interleukin-1 beta (IL-1β), IL-18 levels, miRNA-223 expression and caspase-1 activity were assayed. MFE significantly reduced macroscopic and microscopic scores, colonic levels of TNFR1, NLRP3, p-NFκB p65, TNFα, IL-1β, IL-18, and caspase-1 activity, and showed increased miRNA-223 expression, almost similarly to Sulfa effects. In conclusion, our study provided a novel impact for MFE against AA-induced UC in rats through affecting miRNA-223 expression and halting TNFα/NFκB/NLRP3 inflammatory pathway.
Data structures based on k-mers for querying large collections of sequencing data sets
Authors: Marchet Camille , Boucher Christina , Puglisi Simon J. , Medvedev Paul , Salson Mikaël , Chikhi Rayan
Published: December 2020

High-throughput sequencing data sets are usually deposited in public repositories (e.g., the European Nucleotide Archive) to ensure reproducibility. As the amount of data has reached petabyte scale, repositories do not allow one to perform online sequence searches, yet, such a feature would be highly useful to investigators. Toward this goal, in the last few years several computational approaches have been introduced to index and query large collections of data sets. Here, we propose an accessible survey of these approaches, which are generally based on representing data sets as sets of k-mers. We review their properties, introduce a classification, and present their general intuition. We summarize their performance and highlight their current strengths and limitations.
Reduction of contextual control of conditioned responses by extended Pavlovian training in an insect
Authors: Sato Misato , Álvarez Beatriz , Mizunami Makoto
Published: December 2020

The effect of repetitive training on learned behavior has been an important subject in neuroscience. In instrumental conditioning in mammals, learned action early in training is often goal-driven and controlled by outcome expectancy, but as training progresses, it becomes more habitual and insensitive to outcome devaluation. Similarly, we recently showed in Pavlovian conditioning in crickets (Gryllus bimaculatus) that a conditioned response (CR) is initially sensitive to devaluation of the unconditioned stimulus but becomes insensitive to it after extended training. It is known that habitual responses after extended instrumental training are characterized by a higher context specificity than are initial goal-directed actions in mammals. In this study, we investigated whether this is applicable to Pavlovian conditioning in crickets. In crickets that received a standard amount of training to associate an odor with water reward under illumination, CR under illumination was stronger than that in the dark. In crickets that received extended training under illumination, on the other hand, the level of CR did not differ in different light conditions. Further experiments confirmed that context specificity decreases with the development of behavioral automaticity by extended training, as opposed to findings in instrumental training in mammals. We conclude that the nature of habitual behaviors after extended training differs in different learning systems of animals.
Trends of and implications for the diffusion of lesson study: thematic analysis of WALS2019 conference presentations
Authors: Fang Yanping , Wang Hongyan
Published: December 2020

Purpose

A first post-WALS attempt at a thematic analysis of the conference presentations since its first annual meeting in 2007, this paper aims to achieve two major purposes: first, to capture the trends of spread and diffusion of lesson and learning studies globally and second, to draw useful implications for future conferences.

Design/methodology/approach

A thematic analysis using NVIVO12.0 coding on all forms of conference presentations found in the WALS 2019 Conference Programme was conducted. Representative cases were selected from paper and symposiums sessions to support the claims generated from the analysis.

Findings

The study provides an evidence-based confirmation of the global spread and diffusion of lesson and learning studies. It uncovers findings key to the initial spread and continued diffusion; examines funding as a mechanism enabling university–school research relationships, models of adaptations and issues of sustainability; surfaces the theoretical models and methods adopted in paper and symposia presentations. The current situation, lessons learned and possible implications for future WALS conferences are discussed.

Research limitations/implications

Inform research on practical cases.

Practical implications

Lessons learned are discussed.

Social implications

These are possible implications for future WALS conferences.

Originality/value

The originality lies in its being the first WALS post-conference analysis aiming at identifying substantive themes with potential to draw important implications for future research and subsequent years' conferences.
A novel model of constrictive pericarditis associated with myocardial fibrosis in rats
Authors: Qiao Wei , Xiao Yang‐jie , Wang Xin , Sun Li‐juan , Chen Yi‐xin , Ren Wei‐dong
Published: December 2020

An efficient animal model is fundamental for studies on the underlying mechanisms of constrictive pericarditis (CP). A novel CP rat model was established by pericardial injection composing of lipopolysaccharides (LPS) and talcum powder without thoracotomy. Pathological changes were confirmed by histological staining. E‐flow Doppler of mitral valve, tissue Doppler E′ in the medial mitral annular (E′sep) and the lateral mitral annular (E′lat) were measured to assess ventricular filling function. Circumferential, longitudinal, and radial strains (SC, SL and SR) and the respective strain rates (SrC, SrL and SrR) were analyzed in interventricular septum (IVS) and left ventricular free wall (LVFW). Rat cardiac fibroblasts (CFs) were treated with LPS. The activation of transforming growth factor β1 (TGF‐β1) was confirmed by Q‐PCR and western blot assays. Thickening of pericardium and fibrosis in pericardium and subepicardial myocardium were showed in the model group. Diastolic dysfunction in the CP group was indicated by decreased E′lat and E′lat/E′sep, increased E/E′lat, decreased EFW of SrC and SrL, increased AIVS and decreased E/A of SrC, SrL and SrR. Systolic dysfunction was indicated by decreased SCFW and SLFW in CP rats. The levels of TGF‐β1, p‐Smad2/3, α‐smooth muscle actin (α‐SMA), and collagen‐I/III (COL‐I/III) were increased in the CP group. The increased TGF‐β1 that induced by LPS activated and phosphorylated Smad2/3 resulting in the secretion of α‐SMA and COL‐I/III. This model is of vital importance in studying the pathogenesis of CP.
Opportunistic use of catecholamine neurotransmitters as siderophores to access iron by Pseudomonas aeruginosa
Authors: Perraud Quentin , Kuhn Lauriane , Fritsch Sarah , Graulier Gwenaëlle , Gasser Véronique , Normant Vincent , Hammann Philippe , Schalk Isabelle J.
Published: December 2020

Iron is an essential nutrient for bacterial growth and the cause of a fierce battle between the pathogen and host during infection. Bacteria have developed several strategies to access iron from the host, the most common being the production of siderophores, small iron‐chelating molecules secreted into the bacterial environment. The opportunist pathogen Pseudomonas aeruginosa produces two siderophores, pyoverdine and pyochelin, and is also able to use a wide panoply of xenosiderophores, siderophores produced by other microorganisms. Here, we demonstrate that catecholamine neurotransmitters (dopamine, l‐DOPA, epinephrine and norepinephrine) are able to chelate iron and efficiently bring iron into P. aeruginosa cells via TonB‐dependent transporters (TBDTs). Bacterial growth assays under strong iron‐restricted conditions and with numerous mutants showed that the TBDTs involved are PiuA and PirA. PiuA exhibited more pronounced specificity for dopamine uptake than for norepinephrine, epinephrine and l‐DOPA, whereas PirA specificity appeared to be higher for l‐DOPA and norepinephrine. Proteomic and qRT‐PCR approaches showed pirA transcription and expression to be induced in the presence of all four catecholamines. Finally, the oxidative properties of catecholamines enable them to reduce iron, and we observed ferrous iron uptake via the FeoABC system in the presence of l‐DOPA.
Interweaving the Fabric of Urban Infrastructure: Senegalese City‐making in Rio de Janeiro
Authors: Heil Tilmann
Published: December 2020

This article reveals how newcomers weave their own threads into the fabric of urban infrastructure. Entangling their own with other urban assemblages, newcomers generate multi‐layered dynamics situationally in order to render possible the lives to which they aspire. They forge openings where there seemed none before and keep negative potentialities in check. To offer an ethnography of how the Senegalese presence in Rio de Janeiro has grown dynamically between 2014 and 2019, I draw analytical strength from the double meaning of agencement: the action of interweaving varied socio‐material components—agencer—so that they work together well, and the resulting assemblage of social and material components. Two case studies act as a starting point: how Senegalese came to inhabit an urban architectural landmark and how they regularize their residence status. Their transformative power of city‐making is generated both through the mutual intertwining of a dahira, a religious group of Senegalese migrants, and a diasporic Senegalese association and through the ways in which the Senegalese interweave themselves and their institutionalized collective forms with ever more socio‐material components of the urban space. Beyond the better‐known transnational embeddedness of the Senegalese, their complex infrastructuring practices upon arrival become constitutive of new urban realities, moulding the city fabric of which they are becoming part.
Clinical relevance of partial HPV16/18 genotyping in stratifying HPV‐positive women attending routine cervical cancer screening: a population‐based cohort study
Authors: Gori S , Battagello J , Gustinucci D , Campari C , Zorzi M , Frayle H , Passamonti B , Sartori G , Bulletti S , Fodero C , Cesarini E , Faggiano R , Del Mistro A
Published: December 2020

Objective

To evaluate partial HPV16/18 genotyping as a possible biomarker to select women attending HPV‐based cervical cancer screening at higher risk to be referred to colposcopy.

Design

Population‐based cohort study.

Setting

Organised cervical cancer screening programmes (Italy).

Population

Women with high‐risk HPV infection (period: 2015–2019).

Methods

We analysed the association between partial HPV16/18 genotyping, cytology triage and histologically confirmed diagnosis of high‐grade cervical intraepithelial neoplasia (CIN3+) lesions.

Main outcome measures

Detection rate (DR) and positive predictive value (PPV) for histologically confirmed CIN3+(any episode in the 2 years after baseline); sensitivity for CIN3+and number of colposcopies needed for lesion detection.

Results

The study included 145 437 women screened with HPV testing by the clinically validated COBAS 4800 HPV assay (Roche). Overall, 9601 (6.6%) women were HPV+at baseline; HPV16 and HPV18 were present in 1865 and 594 samples, respectively. The cumulative (baseline plus 1‐year repeat) cytology positivity was 42.8% and high‐grade cytology was significantly higher (P < 0.0001) among women with HPV16 infection at baseline (15.2%). The cumulative CIN3+DR for women with HPV16, HPV18 and other HPV‐type infections was 9.8%, 3.4% and 1.8%, respectively.

Conclusions

Partial HPV16 genotyping may play a role in triage, whereas HPV18 seems to behave much more similarly to the other HPV types and does not provide additional stratification. HPV16 genotyping combined with high‐grade cytology can be envisaged as a triage biomarker in cervical screening to maximise CIN3+detection while minimising colposcopy at baseline or 1‐year repeat.

Tweetable abstract

HPV16 genotyping combined with high‐grade cytology can be used as triage biomarker for CIN3+in HPV‐positive women.