bluuebunny/crossref_metadata_2025 huggingface dataset:
Environmental Screening for Surface SARS-CoV-2 Contamination in Urban High-Touch Areas
Authors: Brazell Lauren Roppolo , Stetz Shawna , Hipp Adam , Taylor Samantha , Stark Nicholas , Jensen Katherine , Islam Juel Md Ariful , Deegan Patrick , Munir Mariya , Schlueter Jessica , Weller Jennifer , Gibas Cynthia
Published: May 2021

The novel human coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 outbreak, which reached pandemic-level infection rates in just a few short months after being identified in late 2019. Early transmission models focused on surface contamination, but current research provides evidence for person-to-person transmission via aerosolized viral particles. As such, the CDC’s guidance has recently been updated to increasingly redirect the focus of prevention methods to aerosol routes. Inhalation of SARS-CoV-2 particles presents the most significant threat of infection to individuals. A secondary route, from hand to mouth, eyes or nose, is likely after contact with a surface contaminated with particles that have settled out of aerosols or been deposited by contaminated hands. Using common molecular detection methods including endpoint and quantitative PCR, we investigated whether there is detectable contamination by SARS-CoV-2 on high-touch surfaces on public transit vehicles and on other high-touch surfaces on a college campus during normal use. Our results indicate that SARS-CoV-2 can be successfully recovered and detected on common high-touch surfaces, albeit in comparatively lower frequencies as public health guidance progressed and more rigorous sanitization procedures were implemented.

Abstract Figure

Graphical abstract created with permission from BioRender.com (2021).
Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis
Authors: Musiu Chiara , Caligola Simone , Fiore Alessandra , Lamolinara Alessia , Frusteri Cristina , Del Pizzo Francesco Domenico , De Sanctis Francesco , Canè Stefania , Adamo Annalisa , Hofer Francesca , Barouni Roza Maria , Grilli Andrea , Zilio Serena , Serafini Paolo , Tacconelli Evelina , Donadello Katia , Gottin Leonardo , Polati Enrico , Girelli Domenico , Polidoro Ildo , Iezzi Piera Amelia , Angelucci Domenico , Capece Andrea , Chen Ying , Shi Zheng-Li , Murray Peter J. , Chilosi Marco , Amit Ido , Bicciato Silvio , Iezzi Manuela , Bronte Vincenzo , Ugel Stefano
Published: May 2021

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-Cov-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homologue in myeloid cells triggered a STAT3-linked, progressive and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.

One sentence summary

FLIP-expressing myeloid cells are key drivers of CRS through aberrant overexpression of STAT3 pathway. STAT3-targeting is effective in mitigating CRS like severe COVID-19.
Clinically relevant shifts in endogenous and exogenous mutational processes proximate to metastasis support local consolidative treatment in EGFR-driven non-small cell lung cancer
Authors: Fisk J. Nicholas , Mahal Amandeep R. , Dornburg Alex , Gaffney Stephen G. , Aneja Sanjay , Contessa Joseph N. , Rimm David , Yu James B. , Townsend Jeffrey P.
Published: May 2021

The progression of cancer—including the acquisition of therapeutic resistance and the fatal metastatic spread of therapy-resistant cell populations—is an evolutionary process that is challenging to monitor between sampling timepoints. Here we apply mutational signature analysis to clinically correlated cancer chronograms to detect and describe the shifting mutational processes caused by both endogenous (e.g. mutator mutation) and exogenous (e.g. therapeutic) factors between tumor sampling timepoints. In one patient, we find that cisplatin therapy can introduce mutations that increase the likelihood of genetic adaptation to subsequent targeted therapeutics. In another patient, we trace the emergence of known driver mutation CTNNB1 S37C to specific detection of defective mismatch repair associated mutational signature SBS3. Metastatic lineages were found to emerge from a single ancestral lineage arising during therapy—a finding that argues for the consideration of local consolidative therapy over other therapeutic approaches in EGFR-positive non-small cell lung cancer. Broadly, these results demonstrate the utility of phylogenetic analysis that incorporates clinical time course and mutational signature detection to inform clinical decision making and retrospective assessment of disease etiology.
Modeling and Predicting Antibody Durability for mRNA-1273 Vaccine for SARS-CoV-2 Variants
Authors: Luo George , Hu Zhongbo , Letterio John J.
Published: May 2021

Recently, the antibody titer levels have been followed in 33 adults who received the mRNA-1273 vaccine for 6 months. With single dose estimated effectiveness of 92.1%, we combine this knowledge with corresponding antibody levels to model and estimate the long-term durability of mRNA-1273 vaccine. Additionally, we integrate studies about differences in antibody neutralization to SARS-CoV-2 variants to understand how variants can affect the durability of the vaccine.

The estimated days after first injection for binding antibodies to fall below levels of those from day 15 is 411 days. The estimated days after first injection to fall below the lower limit of detection of 20 GMTs is 327 days for pseudovirus neutralization and 461 days for live virus neutralization. Our model has pseudovirus neutralization against variant B.1.351 falling below 20 GMT on day 100; variant P.1 on day 202, variant B.1.429 on day 258; and variant B.1.1.7 on day 309.

The data used contains many limitations including the small sample size with older age bias, sensitivity of the neutralization assays, and limited data on variants. Still, we believe mRNA-1273 two dose vaccine can provide over a year of protection against COVID-19 from the initial D614G variant. It is likely by the second year, protection against COVID-19 will fall below single dose efficacy. Therefore, there should be consideration for a booster shot a year after the first set of vaccines. If there is an observed increase in variants with higher resistance such as B.1.351 and P.1, a booster vaccine against the newer variants should be considered to increase protection against resistant variants.
Sex-biased response to and brain cell infection by SARS-CoV-2 in a highly susceptible human ACE2 transgenic model
Authors: Tsai Ching-Yen , Chen Chiung-Ya , Jan Jia-Tsrong , Chou Yu-Chi , Chang Mei-Ling , Lu Lu A , Huang Pau-Yi , Chu Mandy F.-C. , Hsu Tsan-Ting , Hsueh Yi-Ping
Published: May 2021

The COVID-19 pandemic is caused by SARS-CoV-2 infection. Human angiotensin-converting enzyme II (hACE2) has been identified as the receptor enabling SARS-CoV-2 host entry. To establish a mouse model for COVID-19, we generated transgenic mouse lines using the (HS4)2-pCAG-hACE2-HA-(HS4)2transgene cassette, which expresses HA-tagged hACE2 under control of the CAG promoter and is flanked by HS4 insulators. Expression levels of the hACE2 transgene are respectively higher in lung, brain and kidney of our CAG-hACE2 transgenic mice and relatively lower in duodenum, heart and liver. The CAG-hACE2 mice are highly susceptibility to SARS-CoV-2 infection, with 100 PFU of SARS-CoV-2 being sufficient to induce 87.5% mortality at 9 days post-infection and resulting in a sole (female) survivor. Mortality was 100% at the higher titer of 1000 PFU. At lower viral titers, we also found that female mice exposed to SARS-CoV-2 infection suffered much less weight loss than male mice, implying sex-biased responses to SARS-CoV-2 infection. We subjected neuronal cultures to SARS-CoV-2 pseudovirus infection to ascertain the susceptibilities of neurons and astrocytes. Moreover, we observed that expression of SARS-CoV-2 Spike protein alters the synaptic responses of cultured neurons. Our transgenic mice may serve as a model for severe COVID-19 and sex-biased responses to SARS-CoV-2 infection, aiding in the development of vaccines and therapeutic treatments for this disease.
Real-time HRMAS13C NMR of obligately anaerobic cells identifies new metabolic targets in the pathogenClostridioides difficile
Authors: Pavao Aidan , Girinathan Brintha , Peltier Johann , Silva Pamela Altamirano , Dupuy Bruno , Cheng Leo L. , Bry Lynn
Published: May 2021

Anaerobic microbial metabolism drives critical aspects of host-microbiome interactions and supports many economically important industrial applications. Yet, the metabolic pathways of anaerobic bacteria and their associated constraints for maintaining energy and redox balance are often poorly described. We employ High-Resolution Magic Angle Spinning Carbon-13 (13C) Nuclear Magnetic Resonance spectroscopy with dynamic flux balance analysis to resolve real-time metabolism in living cells of the obligately anaerobic pathogenClostridioides difficile. Using13C-labeled carbon sources, we elaborate the time-dependent progression of reductive and oxidative anaerobic fermentation pathways. Analyses identified new integration points for redox and nitrogen coupling between carbohydrate and amino acid metabolism, particularly in the production of13C-alanine from13C-glucose to provide an ammonia sink from co-occurring amino acid fermentation. Analyses conducted in the presence or absence of selenium, a required co-factor for the proline Stickland reductase, demonstrate further capacity to modulate cellular metabolism and resulting metabolites. Findings informed a genome-scale metabolic model ofC. difficile, identifying alanine and associated electron carrier pools as critical metabolic integration points in energy flow and biomass expansion. We illustrate use of HRMAS NMR as a new analytical platform to resolve complex interactions in anaerobic metabolism and inform new metabolic targets to counterC. difficileinfections.
Histone marks are drivers of the splicing changes necessary for an epithelial-to-mesenchymal transition
Authors: Segelle A. , Núñez-Álvarez Y. , Oldfield A. J. , Webb K. M. , Voigt P. , Luco R. F.
Published: May 2021

Cell differentiation and reprogramming depend on coordinated changes in specific alternative splicing events. How these cell type-specific splicing patterns are dynamically modified in response to a stimulus remains elusive. Taking advantage of the epithelial-to-mesenchymal transition (EMT), a reversible cell reprogramming intimately involved in cancer cell invasiveness and metastasis, we found a strong correlation between changes in the alternative splicing of key exons for EMT, such as at theFgfr2andCnntd1loci, and changes in the enrichment levels of specific histone modifications, namely H3K27ac and H3K27me3. Localised CRISPR epigenome editing of these exon-specific histone marks was sufficient to induce changes in splicing capable of recapitulating important aspects of EMT, such as a motile and invasive cell phenotype. Whereas, impairment of the changes in H3K27 marks observed during EMT, using histone deacetylase inhibitors, repressed inclusion of the mesenchymal isoform despite an EMT induction, supporting a driving effect for H3K27 modifications in establishing the new cell type-specific splicing patterns necessary for EMT cell reprogramming. Finally, H3K27 marks were shown to impact splicing by modulating recruitment of the splicing factor PTB to its RNA binding sites, suggesting a direct link between chromatin modifications and the splicing machinery. Taken together, these results prove the causal role of H3K27 marks in driving the dynamic splicing changes necessary for induction of important aspects of EMT. They also prove that chromatin-mediated splicing changes are sufficient to impact the cell’s phenotype, which expands the cell’s toolkit to adapt and respond to diverse stimuli, such as EMT induction.
Functional architecture of neural circuits for leg proprioception inDrosophila
Authors: Chen Chenghao , Agrawal Sweta , Mark Brandon , Mamiya Akira , Sustar Anne , Phelps Jasper S , Lee Wei-Chung Allen , Dickson Barry J , Card Gwyneth M , Tuthill John C
Published: May 2021

To effectively control their bodies, animals rely on feedback from proprioceptive mechanosensory neurons. In theDrosophilaleg, different proprioceptor subtypes monitor joint position, movement direction, and vibration. Here, we investigate how these diverse sensory signals are integrated by central proprioceptive circuits. We find that signals for leg joint position and directional movement converge in second-order neurons, revealing pathways for local feedback control of leg posture. Distinct populations of second-order neurons integrate tibia vibration signals across pairs of legs, suggesting a role in detecting external substrate vibration. In each pathway, the flow of sensory information is dynamically gated and sculpted by inhibition. Overall, our results reveal parallel pathways for processing of internal and external mechanosensory signals, which we propose mediate feedback control of leg movement and vibration sensing, respectively. The existence of a functional connectivity map also provides a resource for interpreting connectomic reconstruction of neural circuits for leg proprioception.
The Immune landscape of pediatric solid tumors
Authors: Sherif Shimaa , Roelands Jessica , Mifsud William , Ahmed Eiman , Mifsud Borbala , Bedognetti Davide , Hendrickx Wouter
Published: May 2021

Background

Immunotherapy is quickly coming to the forefront of cancer treatment; however, the implementation of immunotherapy in solid pediatric cancers, which classically display a low mutational load, is hindered by insufficient understanding of the determinants of cancer immune responsiveness in children. In order to better understand tumor-host interplay, we sought to characterize solid pediatric cancers based on immunological parameters using analytes extracted from gene expression data.

Methods

We used RNAseq data from the publicly available TARGET studies for five pediatric solid tumor types (408 patients): Wilms tumor (WT), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of previously identified immune signatures like the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response associated with favorable prognosis and responsiveness to immunotherapy. We also performed gene set enrichment analysis (ssGSEA) and clustering, using more than 100 immune signatures to define immune subtypes in pediatric tumors and compared the overall survival across subtypes. The expression of immune checkpoints and enrichment of oncogenic pathways were also assessed across the immune subtypes.

Results

The five tumor types showed distinct ICR score distributions. A higher ICR score was associated with better survival in OS and NBL-HR-MYCN_NA, but with poorer survival in WT. The clustering of immune signatures revealed the same five principal modules observed in adult solid tumors: Wound Healing, TGF-B signaling, IFN-G signaling, Macrophages, and Lymphocytes. These modules clustered pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival and was characterized by low enrichment of the wound healing signature, high Th1, low Th2. Conversely, cluster S4 showed the worst survival and highest enrichment of wound healing signature, low Th1, and high Th2. Furthermore, the upregulation of the WNT/Beta-catenin pathway is associated with unfavorable outcomes and lack of T-cell infiltration in OS.

Conclusions

We demonstrated that extracranial solid pediatric tumors could be classified according to their immune disposition, unveiling similarity with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.
Multi-view confocal microscopy enables multiple organ and whole organism live-imaging
Authors: Leroy Olivier , van Leen Eric , Girard Philippe , Villedieu Aurélien , Hubert Christian , Bosveld Floris , Bellaïche Yohanns , Renaud Olivier
Published: May 2021

Understanding how development is coordinated in multiple tissues and gives rise to fully functional organs or whole organisms necessitates microscopy tools. Over the last decade numerous advances have been made in live-imaging, enabling high resolution imaging of whole organisms at cellular resolution. Yet, these advances mainly rely on mounting the specimen in agarose or aqueous solutions, precluding imaging of organisms whose oxygen uptake depends on ventilation. Here, we implemented a multi-view multi-scale microscopy strategy based on confocal spinning disk microscopy, called Multi-View confocal microScopy (MuViScopy). MuViScopy enables live-imaging of multiple organs with cellular resolution using sample rotation and confocal imaging without the need of sample embedding. We illustrate the capacity of MuViScopy by live-imagingDrosophila melanogasterpupal development throughout metamorphosis, highlighting how internal organs are formed and multiple organ development is coordinated. We foresee that MuViScopy will open the path to better understand developmental processes at the whole organism scale in living systems that necessitates gas exchange by ventilation.
TOPLESS promotes plant immunity by repressing auxin signaling and is targeted by the fungal effector Naked1
Authors: Navarrete Fernando , Gallei Michelle , Kornienko Aleksandra E. , Saado Indira , Chia Khong-Sam , Darino Martin A. , Khan Mamoona , Bindics Janos , Djamei Armin
Published: May 2021

In plants, the antagonism between growth and defense is hardwired by hormonal signaling. Perception of Pathogen Associated Molecular Patterns (PAMPs) from invading microorganisms inhibits auxin signaling and growth. Conversely, pathogens manipulate auxin signaling to promote disease, but how this hormone inhibits immunity is not fully understood.Ustilago maydisis a maize pathogen that induces auxin signaling in its host. We characterized anU. maydiseffector protein, Naked1 (Nkd1), that is translocated into the host nucleus. Through its native EAR motif, Nkd1 binds to the transcriptional co-repressors TOPLESS/TOPLESS related (TPL/TPRs) and prevents the recruitment of transcriptional repressors involved in hormonal signaling, leading to de-repression of auxin and jasmonate signaling. Moderate up-regulation of auxin signaling inhibits an early defense response, PAMP-triggered ROS burst. Thus, our findings establish a clear mechanism for auxin-induced pathogen susceptibility. Manipulation of TPL by Nkd1 is evolutionary well balanced as engineered Nkd1 variants with increased expression or increased EAR-mediated TPL/TPR binding trigger typical salicylic acid mediated defense reactions, leading to pathogen resistance.
Biological mechanisms of aging predict age-related disease multimorbidities in patients
Authors: Fraser Helen C , Kuan Valerie , Johnen Ronja , Zwierzyna Magdalena , Hingorani Aroon D , Beyer Andreas , Partridge Linda
Published: May 2021

Genetic, environmental and pharmacological interventions into the aging process can confer resistance to a multiple age-related diseases in laboratory animals, including rhesus monkeys. These findings imply that mechanisms of aging might contribute to patterns of multimorbidity in humans, and hence could be targeted to prevent multiple conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation, and found strong, non-random associations between age-related diseases and aging mechanisms, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age-related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signalling pathway and activity of the ERK1/2 pathway played a significant role across multiple aging mechanisms and multiple, diverse age-related diseases. Mechanisms of aging therefore contribute to multiple age-related diseases and to patterns of human age-related multimorbidity, and could potentially be targeted to prevent more than one age-related condition in the same patient.
Fitness costs of female choosiness in a socially monogamous songbird
Authors: Forstmeier Wolfgang , Wang Daiping , Martin Katrin , Kempenaers Bart
Published: May 2021

Female mate choice is thought to be responsible for the evolution of many extravagant male ornaments and displays, but the costs of being too selective may hinder the evolution of choosiness. Selection against choosiness should be strongest in socially monogamous mating systems, because females may end up without a partner and forego reproduction, especially when many females prefer the same few partners (frequency-dependent selection). Here we quantify the fitness costs of having mating preferences that are difficult to satisfy. We capitalise on the recent discovery that female zebra finches (Taeniopygia guttata) prefer males of familiar song dialect. We measured female fitness in captive breeding colonies in which one third of females were given ample opportunity to choose a mate of their preferred dialect (two thirds of all males; ‘relaxed competition’), while two thirds of the females had to compete over a limited pool of mates they preferred (one third of all males; ‘high competition’). As expected, social pairings were strongly assortative with regard to song dialect. In the high-competition group, 26% of the females remained unpaired, yet they still obtained relatively high fitness by using brood parasitism as an alternative reproductive tactic. Another 31% of high-competition females paired disassortatively for song dialect. These females showed increased levels of extra-pair paternity, mostly with same-dialect males as sires, suggesting that preferences were not abolished after social pairing. However, females that paired disassortatively for song dialect did not have lower reproductive success. Overall, females in the high-competition group reached equal fitness as those that experienced relaxed competition. Our study suggests that alternative reproductive tactics such as egg dumping can help overcome the frequency-dependent costs of being highly selective in a monogamous mating system, thereby facilitating the evolution of female choosiness.
Evaluation of genotoxic and cytogenetic effects of saponins and aluminum hydroxide adjuvant on viral vaccine
Authors: Magnelli Roberta Fiusa , de Cássia Stocco Rita , da Silva Junior Pedro Ismael , Mendonça Ronaldo Zucatelli
Published: May 2021

Bovine papillomavirus (BPV) is the etiological agent of bovine papillomatosis, infectious disease characterized by the presence of benign tumors that can progress to malignancy. The phylogenetic classification of the PVs is performed based on the sequence homology of the Open Reading Frame L1, the most conserved among different viral serotypes. Given the immunogenicity of saponins, it,s has been used as a candidate as adjuvant use. For this reason, the safety of using saponin as an adjuvant has to be better determined to human or veterinary vaccine use. So, this study aimed to evaluate the mutagenic and genotoxic effect of saponins in comparison with the adjuvant widely used aluminum hydroxide using an isolated and purified L1 protein from BPV as model. In this study, genomic lesions, which after processed without repair can result in mutations, were detected by comet assay. Possible damages to genetic material caused by structural chromosomal changes (clastogenesis), as well as chromosomal losses (aneugenesis) were evaluated by the micronucleus test. Both tests were done on polychromatic erythrocytes and Vero cells. The evaluation of apoptosis and necrosis of treated Vero cells was made by Annexin V / PI staining and flow cytometry. The two vaccine products (L1 +Saponin and L1 + Aluminum Hydroxide) showed damages compatible with the positive control in the comet assay and both slightly elevated the micronucleus levels, in the Cell Viability Assay the results with Aluminum Hydroxide were satisfactory, characterizing Aluminum Hydroxide as a safer adjuvant according to the proposed tests, better than the saponins. Some fractions of the saponin extract separated by High Performance Liquid Chromatography were evaluated against genotoxic activity by comet assay, and their identities were confirmed by similarity to the reference standard by mass spectrometry.
Telomere-to-telomere genome assembly ofPhaeodactylum tricornutum
Authors: Giguere Daniel J. , Bahcheli Alexander T. , Slattery Samuel S. , Patel Rushali R. , Flatley Martin , Karas Bogumil J. , Edgell David R. , Gloor Gregory B.
Published: May 2021

Phaeodactylum tricornutumis a marine diatom with a growing genetic toolbox available and is being used in many synthetic biology applications. While most of the genome has been assembled, the currently available genome assembly is not a completed telomere-to-telomere assembly. Here, we used Oxford Nanopore long reads to build a telomere-to-telomere genome forPhaeodactylum tricornutum. We developed a graph-based approach to extract all unique telomeres, and used this information to manually correct assembly errors. In total, we found 25 nuclear chromosomes that comprise all previously assembled fragments, in addition to the chloroplast and mitochondrial genomes. We found that chromosome 19 has filtered long-read coverage and a quality estimate that suggests significantly less haplotype sequence variation than the other chromosomes. This work improves upon the previous genome assembly and provides new opportunities for genetic engineering of this species, including creating designer synthetic chromosomes.
The adenoviral E1B-55k protein present in HEK293 cells mediates abnormal accumulation of key WNT signaling proteins in large cytoplasmic aggregates
Authors: Olsen Petter Angell , Krauss Stefan
Published: May 2021

HEK293 cells are one of the most widely used cell lines in research and HEK293 cells are frequently used as anin vitromodel for studying the WNT signaling pathway. The HEK293 cell line was originally established by transfection of human embryonic kidney cells with sheared adenovirus 5 DNA and it is known that that HEK293 cells stably express the adenoviral E1A and E1B-55k proteins. Here we show that HEK293 cells display an unexpected distribution of key components of the WNT/β-catenin signaling pathway where AXIN1, APC, DVL2 and tankyrase are all co-localized in large spherical cytoplasmic aggregates. The cytoplasmic aggregates are enclosed by a narrow layer of the adenoviral E1B-55k protein. Reduction of E1B-55k protein levels leads to disappearance of the cytoplasmic aggregates thus corroborating an essential role of the E1B-55k protein in mediating the formation of the aggregates. Furthermore, HEK293 cells with reduced E1B-55k protein levels display reduced levels of transcriptional activation of WNT/β-catenin signaling upon stimulation by the Wnt3A agonist. The demonstrated influence of the E1B-55k protein on the cellular localization of WNT/β-catenin signaling components and on transcriptional regulation of WNT/β-catenin signaling asks for caution in the interpretation of data derived from the HEK293 cell line.
Systematic temporal analysis of peripheral blood transcriptomes usingTrendCatcheridentifies early and persistent neutrophil activation as a hallmark of severe COVID-19
Authors: Wang Xinge , Sanborn Mark , Dai Yang , Rehman Jalees
Published: May 2021

Studying temporal gene expression shifts during disease progression provides important insights into the biological mechanisms that distinguish adaptive and maladaptive responses. Existing tools for the analysis of time course transcriptomic data are not designed to optimally identify distinct temporal patterns when analyzing dynamic differentially expressed genes (DDEGs). Moreover, there is a lack of methods to assess and visualize the temporal progression of biological pathways mapped from time course transcriptomic datasets. In this study, we developed an open-source R packageTrendCatcher(https://github.com/jaleesr/TrendCatcher), which applies the smoothing spline ANOVA model and break point searching strategy to identify and visualize distinct dynamic transcriptional gene signatures and biological processes from longitudinal datasets. We usedTrendCatcherto perform a systematic temporal analysis of COVID-19 peripheral blood transcriptomes, including bulk RNA-seq and scRNA-seq time course data.TrendCatcheruncovered the early and persistent activation of neutrophils and coagulation pathways as well as impaired type I interferon (IFN-I) signaling in circulating cells as a hallmark of patients who progressed to severe COVID-19, whereas no such patterns were identified in individuals receiving SARS- CoV-2 vaccinations or patients with mild COVID-19. These results underscore the importance of systematic temporal analysis to identify early biomarkers and possible pathogenic therapeutic targets.
Multivalent interactions make adherens junction-cytoskeletal linkage robust during morphogenesis
Authors: Perez-Vale Kia Z. , Yow Kristi D. , Byrnes Amy E. , Finegan Tara M. , Slep Kevin C. , Peifer Mark
Published: May 2021

Embryogenesis requires cells to change shape and move without disrupting epithelial integrity. This requires robust, responsive linkage between adherens junctions and the actomyosin cytoskeleton. UsingDrosophilamorphogenesis we define molecular mechanisms mediating junction-cytoskeletal linkage and explore the role of mechanosensing. We focus on the junction-cytoskeletal linker Canoe, a multidomain protein. We engineered thecanoelocus to define how its domains mediate its mechanism of action. To our surprise, the PDZ and FAB domains, which we thought connected junctions and F-actin, are not required for viability or mechanosensitive recruitment to junctions under tension. The FAB domain stabilizes junctions experiencing elevated force, but in its absence most cells recover, suggesting redundant interactions. In contrast, the Rap1-binding RA domains are critical for all Cno functions and for enrichment at junctions under tension. This supports a model in which junctional robustness derives from a large protein network assembled via multivalent interactions, with proteins at network nodes and some node connections more critical than others.
Single gene initiates evolution of epithelial architecture and function
Authors: Noeske Viola , Caglayan Emre , Lemke Steffen
Published: May 2021

Epithelial monolayers are a hallmark of the architecture of metazoan tissues: they provide stability, serve as barriers, and fold into organs. Epithelial cells vary in shape, ranging from flat and spread out to tall and slim. Dynamic epithelial shape changes have been explored in the context of tissue folding, where local cytoskeletal modulations cause epithelial bending and folding. Comparatively little is known about how entire tissues are transformed from a short to tall architecture. Here we show that shape regulation in epithelia can be governed by the activity of a single gene. We use a comparative approach in distantly related flies to experimentally decode the developmental program that directs the formation of columnar epithelia in the blastoderm and thus determines the physiological features of the resulting epithelium. We uncover an evolutionary novel, membrane-associated protein that emerged in flies and triggered a new development program, the cuboidal-to-columnar transformation of epithelial tissues. slow-as-molasses (slam) encodes a Dia/F-actin regulator that exploits an intrinsic morphological plasticity of cells to transform tissues. Our findings demonstrate that a single, newly emerged factor that amplifies its activity in epithelia provides the basis for adaptation and initiates the evolution of novel developmental programs.
Wikidata and the bibliography of life
Authors: Page Roderic D. M.
Published: May 2021

Biological taxonomy rests on a long tail of publications spanning nearly three centuries. Not only is this literature vital to resolving disputes about taxonomy and nomenclature, for many species it represents a key source - indeed sometimes the only source - of information about that species. Unlike other disciplines such as biomedicine, the taxonomic community lacks a centralised, curated literature database (the “bibliography of life”). This paper argues that Wikidata can be that database as it has flexible and sophisticated models of bibliographic information, and an active community of people and programs (“bots”) adding, editing, and curating that information. The paper also describes a tool to visualise and explore bibliography information in Wikidata and how it links to both taxa and taxonomists.
Explainable Sleep Stage Classification with Multimodal Electrophysiology Time-series
Authors: Ellis Charles A. , Zhang Rongen , Carbajal Darwin A. , Miller Robyn L. , Calhoun Vince D. , Wang May D.
Published: May 2021

Many automated sleep staging studies have used deep learning approaches, and a growing number have used multimodal data to improve their classification performance. However, few studies using multimodal data have provided model explainability. Some have used traditional ablation approaches that “zero out” a modality. However, the samples that result from this ablation are unlikely to be found in real electroencephalography (EEG) data, which could adversely affect the importance estimates that result. Here, we train a convolutional neural network for sleep stage classification with EEG, electrooculograms (EOG), and electromyograms (EMG) and propose an ablation approach that replaces each modality with values that approximate the line-related noise commonly found in electrophysiology data. The relative importance that we identify for each modality is consistent with sleep staging guidelines, with EEG being important for most sleep stages and EOG being important for Rapid Eye Movement (REM) and nonREM stages. EMG showed low relative importance across classes. A comparison of our approach with a “zero out” ablation approach indicates that while the importance results are consistent for the most part, our method accentuates the importance of modalities to the model for the classification of some stages like REM (p < 0.05). These results suggest that a careful, domain-specific selection of an ablation approach may provide a clearer indicator of modality importance. Further, this study provides guidance for future research on using explainability methods with multimodal electrophysiology data.
Metamodal Coupling of Vibrotactile and Auditory Speech Processing Systems Through Matched Stimulus Representations
Authors: Damera Srikanth R. , Malone Patrick S. , Stevens Benson W. , Klein Richard , Eberhardt Silvio P. , Auer Edward T. , Bernstein Lynne E. , Riesenhuber Maximilian
Published: May 2021

It has been postulated that the brain is organized by “metamodal”, sensory-independent cortical modules implementing particular computations, leading to the intriguing hypothesis that brain areas can perform tasks (such as word recognition) not just in “standard” sensory modalities but also in novel sensory modalities. Yet, evidence for this theory, especially in neurotypical subjects, has been variable. We hypothesized that effective metamodal engagement of a brain area requires congruence between the novel and standard sensory modalities not only at the task level (e.g., “word recognition”) but critically also a match at the algorithmic level (in Marr’s terminology), i.e., at the level of neural representation of the information of interest. To test this hypothesis, we trained participants to recognize vibrotactile versions of auditory words using two encoding schemes. The vocoded approach preserved the dynamics and representational similarities of auditory speech while the token-based approach used an abstract phoneme-based code. Although both groups learned the vibrotactile word recognition task, only in the vocoded group did trained vibrotactile stimuli recruit the auditory speech network and lead to increased coupling between somatosensory and auditory speech areas. In contrast, the token-based encoding appeared to rely on paired-associate learning. Thus, matching neural input representations is a critical factor for assessing and leveraging the metamodal potential of cortical modules.
SARS-CoV-2 variant B.1.617 is resistant to Bamlanivimab and evades antibodies induced by infection and vaccination
Authors: Hoffmann Markus , Hofmann-Winkler Heike , Krüger Nadine , Kempf Amy , Nehlmeier Inga , Graichen Luise , Sidarovich Anzhalika , Moldenhauer Anna-Sophie , Winkler Martin S. , Schulz Sebastian , Jäck Hans-Martin , Stankov Metodi V. , Behrens Georg M. N. , Pöhlmann Stefan
Published: May 2021

The emergence of SARS-CoV-2 variants threatens efforts to contain the COVID-19 pandemic. The number of COVID-19 cases and deaths in India has risen steeply in recent weeks and a novel SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the ACE2 receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyzed whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 entered two out of eight cell lines tested with slightly increased efficiency and was blocked by entry inhibitors. In contrast, B.1.617 was resistant against Bamlanivimab, an antibody used for COVID-19 treatment. Finally, B.1.617 evaded antibodies induced by infection or vaccination, although with moderate efficiency. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.
Young Adults Recruit Similar Motor Modules Across Walking, Turning, and Chair Transfers
Authors: Carey Hannah D. , Liss Daniel , Allen Jessica L.
Published: May 2021

Moving about in the world during daily life requires executing and successfully shifting between a variety of functional tasks, such as arising from a chair or bed, walking, turning, and navigating stairs, etc. Moreover, moving about during daily life requires not only navigating between different functional tasks but also performing these tasks in the presence of mental distractions. However, little is known about underlying neuromuscular control for executing and shifting between these different tasks. In this study, we investigated muscle coordination across walking, turning, and chair transfers by applying motor module (aka muscle synergy) analysis to the Timed-Up-and-Go (TUG) test with and without a secondary cognitive dual task. We found that healthy young adults recruit a small set of common motor modules across the subtasks of the TUG test and that their composition is robust to cognitive distraction. Instead, cognitive distraction impacted motor module activation timings such that they became more consistent. This work is the first to demonstrate motor module generalization across multiple tasks that are both functionally different and crucial for healthy mobility. Overall, our results suggest that the central nervous system may draw from a “library” of modular control strategies to navigate the variety of movements and cognitive demands required of daily life.

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We demonstrated that healthy young adults recruit a small set of motor modules across subtasks of the Timed-Up-and-Go test (i.e., walking, turning, and chair transfers). Moreover, we showed that motor module composition, but not activation timing, is robust to cognitive distractions. These results support the hypothesis that healthy young adults recruit from a “library” of motor modules and modulate their activation timing to meet the different mechanical and cognitive demands required to navigate daily life.
Combined effect of cell geometry and polarity domains determines the orientation of unequal division
Authors: Godard Benoit G. , Dumollard Rémi , Heisenberg Carl-Philipp , McDougall Alex
Published: May 2021

Cell division orientation is thought to result from a competition between cell geometry and polarity domains controlling the position of the mitotic spindle during mitosis. Depending on the level of cell shape anisotropy or the strength of the polarity domain, one dominates the other and determines the orientation of the spindle. Whether and how such competition is also at work to determine unequal cell division (UCD), producing daughter cells of different size, remains unclear. Here, we show that cell geometry and polarity domains cooperate, rather than compete, in positioning the cleavage plane during UCDs in early ascidian embryos. We found that the UCDs and their orientation at the ascidian third cleavage rely on the spindle tilting in an anisotropic cell shape, and cortical polarity domains exerting different effects on spindle astral microtubules. By systematically varying mitotic cell shape, we could modulate the effect of attractive and repulsive polarity domains and consequently generate predicted daughter cell size asymmetries and position. We therefore propose that the spindle position during UCD is set by the combined activities of cell geometry and polarity domains, where cell geometry modulates the effect of cortical polarity domain(s).

Graphical abstract

Highlight

Spindle tilting in anisotropic cell shape induces unequal cell division

Cortical polarity domain can exert attractive or repulsive effect on spindle

Cell geometry and polarity domain cooperate to position the spindle

Cell geometry modulates the effect of polarity domain
Local rather than global H3K27me3 dynamics associates with differential gene expression inVerticillium dahliae
Authors: Kramer H. Martin , Seidl Michael F. , Thomma Bart P.H.J. , Cook David E.
Published: May 2021

Differential growth conditions typically trigger global transcriptional responses in filamentous fungi. Such fungal responses to environmental cues involve epigenetic regulation, including chemical histone modifications. It has been proposed that conditionally expressed genes, such as those that encode secondary metabolites but also effectors in pathogenic species, are often associated with a specific histone modification, lysine27 methylation of H3 (H3K27me3). However, thus far no analyses on the global H3K27me3 profiles have been reported under differential growth conditions in order to assess if H3K27me3 dynamics governs differential transcriptional. Using ChIP- and RNA-sequencing data from the plant pathogenic fungusVerticillium dahliaegrown in threein vitrocultivation media, we now show that a substantial number of the identified H3K27me3 domains globally display stable profiles among these growth conditions. However, we do observe local quantitative differences in H3K27me3 ChIP-seq signal that associate with a subset of differentially transcribed genes between media. Comparing thein vitroresults to expression during plant infection suggests thatin planta-induced genes may require chromatin remodelling to achieve expression. Overall, our results demonstrate that some loci display H3K27me3 dynamics associated with concomitant transcriptional variation, but many differentially expressed genes are associated with stable H3K27me3 domains. Thus, we conclude that while H3K27me3 is required for transcriptional repression, it does not appear that transcriptional activation requires global erasure of H3K27me3. We propose that the H3K27me3 domains that do not undergo dynamic methylation may contribute to transcription through other mechanisms or may serve additional genomic regulatory functions.
Diversity of funnel plasmodesmata in angiosperms: the impact of geometry on plasmodesmal resistance
Authors: Ostermeyer Grayson P. , Jensen Kaare H. , Franzen Aslak R. , Peters Winfried S. , Knoblauch Michael
Published: May 2021

In most plant tissues, threads of cytoplasm, or plasmodesmata, connect the protoplasts via pores in the cell walls. This enables symplasmic transport, for instance in phloem loading, transport, and unloading. Importantly, the geometry of the wall pore limits the size of the particles that may be transported, and also (co-)defines plasmodesmal resistance to diffusion and convective flow. However, quantitative information on transport through plasmodesmata in non-cylindrical cell wall pores is scarce. We have found conical, funnel-shaped cell wall pores in the phloem-unloading zone in growing root tips of five eudicot and two monocot species, specifically between protophloem sieve elements and phloem pole pericycle cells. 3D reconstructions by electron tomography suggested that funnel plasmodesmata possess a desmotubule but lack tethers to fix it in a central position. Model calculations showed that both diffusive and hydraulic resistance decrease drastically in conical cell wall pores compared to cylindrical channels, even at very small opening angles. Notably, the effect on hydraulic resistance was relatively larger. We conclude that funnel plasmodesmata generally are present in specific cell-cell interfaces in angiosperm roots, where they appear to facilitate symplasmic phloem unloading. Interestingly, cytosolic sleeves of most plasmodesmata reported in the literature do not resemble straight annuli but possess variously shaped widenings. Our evaluations suggest that widenings too small for identification on electron micrographs may drastically reduce the hydraulic and diffusional resistance of these pores. Consequently, theoretical models assuming cylindrical symmetries will underestimate plasmodesmal conductivities.
3-D Vascularized Breast Cancer Model to Study the Role of Osteoblast in Formation of a Pre-Metastatic Niche
Authors: Rimal Rahul , Desai Prachi , Marquez Andrea Bonnin , Sieg Karina , Marquardt Yvonne , Singh Smriti
Published: May 2021

Breast cancer cells (BCCs) preferentially metastasize to bone. It is known that BCCs remotely primes the distant bone site prior to metastasis. However, the reciprocal influence of bone cells on the primary tumor is relatively overlooked. Here, to study the bone-tumor paracrine influence, a tri-cellular 3-D vascularized breast cancer tissue (VBCTs) model is engineered which comprised MDA-MB231, a triple-negative breast cancer cells (TNBC), fibroblasts, and endothelial cells. The VBCTs are indirectly co-cultured with osteoblasts (OBs), thereby constituting a complex quad-cellular tumor progression model. MDA-MB231 alone and in conjunction with OBs led to abnormal vasculature and reduced vessel density but enhanced VEGF production. A total of 1476 significantly upregulated and 775 downregulated genes are identified in the VBCTs exposed to OBs. HSP90N, CYCS, RPS27A, and EGFR are recognized as upregulated hub-genes. Kaplan Meier plot shows HSP90N to have a significant outcome in TNBC patient survivability. Furthermore, compared to cancer tissues without vessels, gene analysis recognized 1278 significantly upregulated and 566 downregulated genes in VBCTs. DKK1, CXCL13, C3 protein and BMP4 are identified to be downregulated hub genes in VBCTs. Together, a multi-cellular breast cancer model and culture protocols are established to study pre-metastatic events in the presence of OBs.