bluuebunny/crossref_metadata_2025 huggingface dataset:
Microenvironment Impacts the Molecular Architecture and Interactivity of Resident Cells in Marmoset Brain
Authors: Lin Jing-Ping , Kelly Hannah M. , Song Yeajin , Kawaguchi Riki , Geschwind Daniel H. , Jacobson Steven , Reich Daniel S.
Published: January 2021

The microenvironments of the brain consist of specialized cell types that together influence physiological functions in health and pathological outcomes in disease. Despite apparent differences in the density of neurons and oligodendrocytes in various milieus, such as gray matter (GM) and white matter (WM), the extent of structural and functional heterogeneity of other resident cells remains unclear. We profiled RNA in ~500,000 nuclei from 19 tissue types across the central nervous system of the healthy adult common marmoset (Callithrix jacchus) and mapped 87 identified subclusters (including neurons, glia, and vasculature) spatially onto a 3D MRI atlas. We performed cross-species comparison, explored regulatory pathways, surveyed cellular determinants of neurological disorders, and modeled regional intercellular communication. We found spatially segregated microglia, oligodendrocyte lineage cells, and astrocytes in WM and GM. WM-glia are diverse, are enriched with genes involved in stimulus response and biomolecule modification, and interact with other resident cells more extensively than their GM counterparts. GM-glia preserve the expression of developmental morphogens into adulthood and share 6 differentially enriched transcription factors that restrict the transcriptome complexity. Our work in marmoset, an experimentally tractable animal model with >5 times more WM volume and complexity than mouse, identifies novel WM-glia subtypes and their contributions to different neurological disorders. A companionCallithrix jacchusPrimate Cell Atlas (CjPCA) is available through an online portalhttps://cjpca.ninds.nih.govto facilitate data exploration.
GLUER: integrative analysis of single-cell omics and imaging data by deep neural network
Authors: Peng Tao , Chen Gregory M. , Tan Kai
Published: January 2021

Single-cell omics assays have become essential tools for identifying and characterizing cell types and states of complex tissues. While each single-modality assay reveals distinctive features about the sequenced cells, true multi-omics assays are still in early stage of development. This notion signifies the importance of computationally integrating single-cell omics data that are conducted on various samples across various modalities. In addition, the advent of multiplexed molecular imaging assays has given rise to a need for computational methods for integrative analysis of single-cell imaging and omics data. Here, we present GLUER (inteGrative anaLysis of mUlti-omics at single-cEllResolution), a flexible tool for integration of single-cell multi-omics data and imaging data. Using multiple true multi-omics data sets as the ground truth, we demonstrate that GLUER achieved significant improvement over existing methods in terms of the accuracy of matching cells across different data modalities resulting in ameliorating downstream analyses such as clustering and trajectory inference. We further demonstrate the broad utility of GLUER for integrating single-cell transcriptomics data with imaging-based spatial proteomics and transcriptomics data. Finally, we extend GLUER to leverage true cell-pair labels when available in true multi-omics data, and show that this approach improves co-embedding and clustering results. With the rapid accumulation of single-cell multi-omics and imaging data, integrated data holds the promise of furthering our understanding of the role of heterogeneity in development and disease.
Expression and manufacturing of protein therapeutics in spirulina
Authors: Jester Benjamin , Zhao Hui , Gewe Mesfin , Adame Thomas , Perruzza Lisa , Bolick David , Agosti Jan , Khuong Nhi , Kuestner Rolf , Gamble Caitlin , Cruickshank Kendra , Ferrara Jeremy , Lim Rachelle , Paddock Troy , Brady Colin , Ertel Stacey , Zhang Mia , Tasch Michael , Saveria Tracy , Doughty David , Marshall Jacob , Carrieri Damian , Lee Jamie , Goetsch Lauren , Dang Jason , Sanjaya Nathaniel , Fletecher David , Martinez Anissa , Kadis Bryce , Sigmar Kristjian , Afreen Esha , Nguyen Tammy , Randolph Amanda , Taber Alexandria , Krzeszowski Ashley , Robinett Brittney , Grassi Fabio , Guerrant Richard , Spigarelli Michael , Takeuchi Ryo , Finrow Brian , Behnke Craig , Roberts James
Published: January 2021

Arthrospira platensis(commonly known as spirulina) is a photosynthetic cyanobacterium1. It is a highly nutritious food that has been consumed for decades in the US, and even longer by indigenous cultures2. Its widespread use as a safe food source and proven scalability have driven frequent attempts to convert it into a biomanufacturing platform. But these were repeatedly frustrated by spirulina’s genetic intractability. We report here efficient and versatile genetic engineering methodology for spirulina that allows stable expression of bioactive protein therapeutics at high levels. We further describe large-scale, indoor cultivation and downstream processing methods appropriate for the manufacturing of biopharmaceuticals in spirulina. The potential of the platform is illustrated by pre-clinical development and human testing of an orally delivered antibody therapeutic against campylobacter, a major cause of infant mortality in the developing world and a growing antibiotic resistance threat3,4. This integrated development and manufacturing platform blends the safety of food-based biotechnology with the ease of genetic manipulation, rapid growth rates and high productivity characteristic of microbial platforms. These features combine for exceptionally low-cost production of biopharmaceuticals to address medical needs that are unfeasible with current biotechnology platforms.
Reagent-free Raman and quantitative phase imaging offer a unique morpho-molecular platform for recognition of malignancy and stages of B-cell acute lymphoblastic leukemia
Authors: Paidi Santosh Kumar , Raj Piyush , Bordett Rosalie , Zhang Chi , Karandikar Sukrut Hemant , Pandey Rishikesh , Barman Ishan
Published: January 2021

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies which account for nearly one-third of all pediatric cancers. The current diagnostic assays are time-consuming, labor-intensive, and require expensive reagents. Here, we report a label-free approach featuring diffraction phase imaging and Raman microscopy that can retrieve both morphological and molecular attributes for label-free optical phenotyping of individual B cells. By investigating leukemia cell lines of early and late stages along with the healthy B cells, we show that phase image can capture subtle morphological differences among the healthy, early, and late stages of leukemic cells. By exploiting its biomolecular specificity, we demonstrate that Raman microscopy is capable of accurately identifying not only different stages of leukemia cells, but also individual cell lines at each stage. Overall, our study provides a rationale for employing this hybrid modality to screen leukemia cells using the widefield QPI and using Raman microscopy for accurate differentiation of early and late-stage phenotypes. This contrast-free and rapid diagnostic tool exhibits great promise for clinical diagnosis and staging of leukemia in the near future.
Mechanism of Viral Glycoprotein Targeting by Membrane-associated-RING-CH Proteins
Authors: Lun Cheng Man , Waheed Abdul A. , Majadly Alhlam , Powell Nicole , Freed Eric O.
Published: January 2021

An emerging class of cellular inhibitory proteins has been identified that targets viral glycoproteins. These include the membrane-associated RING-CH (MARCH) family of E3 ubiquitin ligases that, among other functions, downregulate cell-surface proteins involved in adaptive immunity. The RING-CH domain of MARCH proteins is thought to function by catalyzing the ubiquitination of the cytoplasmic tails (CTs) of target proteins, leading to their degradation. MARCH proteins have recently been reported to target retroviral envelope glycoproteins (Env) and vesicular stomatitis virus G glycoprotein (VSV-G). However, the mechanism of antiviral activity remains poorly defined. Here we show that MARCH8 antagonizes the full-length forms of HIV-1 Env, VSV-G, Ebola virus glycoprotein (EboV-GP), and the spike (S) protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) thereby impairing the infectivity of virions pseudotyped with these viral glycoproteins. This MARCH8-mediated targeting of viral glycoproteins requires the E3 ubiquitin ligase activity of the RING-CH domain. We observe that MARCH8 protein antagonism of VSV-G is CT dependent. In contrast, MARCH8-mediated targeting of HIV-1 Env, EboV-GP and SARS-CoV-2 S protein by MARCH8 does not require the CT, suggesting a novel mechanism of MARCH-mediated antagonism of these viral glycoproteins. Confocal microscopy data demonstrate that MARCH8 traps the viral glycoproteins in an intracellular compartment. We observe that the endogenous expression ofMARCH8in several relevant human cell types is rapidly inducible by type I interferon. These results help to inform the mechanism by which MARCH proteins exert their antiviral activity and provide insights into the role of cellular inhibitory factors in antagonizing the biogenesis, trafficking, and virion incorporation of viral glycoproteins.

Importance

Viral envelope glycoproteins are an important structural component on the surface of enveloped viruses that direct virus binding and entry and also serve as targets for the host adaptive immune response. In this study, we investigate the mechanism of action of the MARCH family of cellular proteins that disrupt the trafficking and virion incorporation of viral glycoproteins across several virus families. This research provides novel insights into how host cell factors antagonize viral replication, perhaps opening new avenues for therapeutic intervention in the replication of a diverse group of highly pathogenic enveloped viruses.
Evidence of Chelonid Herpesvirus 5 (ChHV5) in Green Turtles (Chelonia mydas) from Sabah, Borneo
Authors: Loganathan Aswini Leela , Palaniappan Pushpa , Subbiah Vijay Kumar
Published: January 2021

Fibropapillomatosis (FP) is characterized by cutaneous tumours and is associated with Chelonid herpesvirus 5 (ChHV5), an alphaherpesvirus from the family Herpesviridae. Here, we provide the first evidence of ChHV5-associated FP in endangered Green turtles (Chelonia mydas) from Sabah, which is located at the northern region of Malaysian Borneo. The aims of this study were firstly, to determine the presence of ChHV5 in both tumour exhibiting and tumour-free turtles using molecular techniques and secondly, to determine the phylogeography of ChHV5 in Sabah. We also aim to provide evidence of ChHV5 infection through histopathological examinations. A total of 115 Green turtles were sampled from Mabul Island, Sabah. We observed three Green turtles that exhibited FP tumours and were positive for ChHV5.In addition, six clinically healthy turtles were also positive for the virus based on Polymerase Chain Reaction of three viral genes (Capsid protein gene UL18, Glycoprotein H gene UL22 and Glycoprotein B gene UL27). The prevalence of the ChHV5 was 5.22% in asymptomatic Green turtles. Epidermal intranuclear inclusions were identified in tumour lesions upon histopathological examination. Thus, the emergence of ChHV5 in Green turtle in the waters of Sabah could indicate a possible threat to sea turtle populations in the future and requires further monitoring of the populations along the Bornean coast.
Single-Cell Proteomics Defines the Cellular Heterogeneity of Localized Prostate Cancer
Authors: De Vargas Roditi Laura , Jacobs Andrea , Rueschoff Jan H. , Bankhead Pete , Chevrier Stephane , Jackson Hartland W. , Hermanns Thomas , Fankhauser Christian D. , Poyet Cedric , Chun Felix , Rupp Niels J. , Tschaebunin Alexandra , Bodenmiller Bernd , Wild Peter J.
Published: January 2021

Localized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. The aim of this study was to identify novel prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated immune cell infiltrates by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1,6 million cells from 58 men with localized prostate cancer. To perform this task, we proposed a novel computational pipeline, Franken, which showed unprecedented combination of performance, sensitivity and scalability for high dimensional clustering compared to state of the art methods. We were able to describe subpopulations of immune, stromal, and prostate cells, including unique changes occurring in tumor tissues and high grade disease providing insights into the coordinated progression of prostate cancer. Our results further indicated that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease, which were confirmed through imaging. Our methodology could be used to discover novel prognostic biomarkers to personalize treatment and improve outcomes.
A high-content platform for physiological profiling and unbiased classification of individual neurons
Authors: DuBreuil Daniel M. , Chiang Brenda , Zhu Kevin , Lai Xiaofan , Flynn Patrick , Sapir Yechiam , Wainger Brian J.
Published: January 2021

High-throughput physiological assays often lose single cell resolution, precluding subtype-specific analyses of neuronal activation mechanism and drug effects. Here, we demonstrate APPOINT, Automated Physiological Phenotyping Of Individual Neuronal Types. This physiological assay platform combines calcium imaging, robotic liquid handling, and automated analysis to generate physiological activation profiles of single neurons at a large scale. Using unbiased techniques, we quantify responses to multiple sequential stimuli, enabling subgroup identification by physiology and probing of distinct mechanisms of neuronal activation within subgroups. Using APPOINT, we quantify primary sensory neuron activation by metabotropic receptor agonists and identify potential contributors to pain signaling. Furthermore, we expand the role of neuroimmune interactions by showing that human serum can directly activate sensory neurons, elucidating a new potential pain mechanism. Finally, we apply APPOINT to develop a high-throughput, all-optical approach for quantification of activation threshold and pharmacologically separate the contributions of distinct ion channel subsets to optical activation.
Hydrodynamic stress and phenotypic plasticity of the zebrafish regenerating fin
Authors: Dagenais Paule , Blanchoud Simon , Pury David , Pfefferli Catherine , Aegerter-Wilmsen Tinri , Aegerter Christof M. , Jaźwińska Anna
Published: January 2021

Understanding how extrinsic factors modulate genetically encoded information to produce a specific phenotype is of prime scientific interest. In particular, the feedback mechanism between abiotic forces and locomotory organs during morphogenesis to achieve efficient movement is a highly relevant example of such modulation. The study of this developmental process can provide unique insights on the transduction of cues at the interface between physics and biology. Here, we take advantage of the natural ability of adult zebrafish to regenerate their amputated fins to assess its morphogenic plasticity upon external modulations. Using a variety of surgical and chemical treatments, we are able to induce phenotypic responses to the structure of the fin. In particular, fin cleft depth and the bifurcation of the bony rays are modulated by the surface area of the stump. To dissect the role of mechanotransduction in this process, we investigate the patterns of hydrodynamic forces acting on the surface of a zebrafish fin during regeneration by using particle tracking velocimetry on a range of biomimetic hydrofoils. This experimental approach enables us to quantitatively compare hydrodynamic stress distributions over flapping fins of varying sizes and shapes. As a result, viscous shear stress acting on the tip of the fin and the resulting internal tension are proposed as suitable signals for guiding the regulation of ray growth dynamics and branching pattern. Our findings suggest that mechanical forces are involved in the fine-tuning of the locomotory organ during fin morphogenesis.
Saccades, attentional orienting and disengagement: the effects of anodal tDCS over right posterior parietal cortex (PPC) and frontal eye field (FEF)
Authors: Diana Lorenzo , Pilastro Patrick , Aiello Edoardo N. , Eberhard-Moscicka Aleksandra K. , Müri René M. , Bolognini Nadia
Published: January 2021

In the present work, we applied anodal transcranial direct current stimulation (tDCS) over the posterior parietal cortex (PPC) and frontal eye field (FEF) of the right hemisphere in healthy subjects to modulate attentional orienting and disengagement in a gap-overlap task. Both stimulations led to bilateral improvements in saccadic reaction times (SRTs), with larger effects for gap trials. However, analyses showed that the gap effect was not affected by tDCS. Importantly, we observed significant effects of baseline performance that may mediate side- and task-specific effects of brain stimulation.
Large Organellar Changes Occur during Mild Heat Shock in Yeast
Authors: Keuenhof Katharina , Berglund Lisa Larsson , Hill Sandra Malmgren , Schneider Kara L , Widlund Per O , Nyström Thomas , Höög Johanna L
Published: January 2021

When the temperature is increased, the heat shock response is activated to protect the cellular environment. The transcriptomics and proteomics of this process are intensively studied, while information about how the cell responds structurally to heat stress is mostly lacking. Here,Saccharomyces cerevisiaewere subjected to a mild continuous heat shock and intermittently cryo-immobilized for electron microscopy. Through measuring changes in all distinguishable organelle numbers, sizes, and morphologies in over 2400 electron micrographs a major restructuring of the cell’s internal architecture during the progressive heat shock was revealed. The cell grew larger but most organelles within it expanded even more. Organelles responded to heat shock at different times, both in terms of size and number, and adaptations of certain organelles’ morphology were observed. Multivesicular bodies grew to almost 170% in size, indicating a previously unknown involvement in the heat shock response. A previously undescribed electron translucent structure accumulated close to the plasma membrane during the entire time course. This all-encompassing approach provides a detailed chronological progression of organelle adaptation throughout the cellular stress response.

Summary statement

Exposure to mild heat shock leads to large quantifiable changes in the cellular ultrastructure of yeast, shows involvement of MVBs in the heat shock response and the apparition of novel structures.
Separate neural dynamics underlying the acquisition of different auditory category structures
Authors: Feng Gangyi , Gan Zhenzhong , Yi Han Gyol , Ell Shawn W. , Roark Casey L. , Wang Suiping , Wong Patrick C. M. , Chandrasekaran Bharath
Published: January 2021

Current models of auditory category learning argue for a rigid specialization of hierarchically organized regions that are fine-tuned to extracting and mapping acoustic dimensions to categories. We test a competing hypothesis: the neural dynamics of emerging auditory representations are driven by category structures and learning strategies. We designed a category learning experiment where two groups of learners learned novel auditory categories with identical dimensions but differing category structures: rule-based (RB) and information-integration (II) based categories. Despite similar learning accuracies, strategies and cortico-striatal systems processing feedback differed across structures. Emergent neural representations of category information within an auditory frontotemporal pathway exclusively for the II learning task. In contrast, the RB task yielded neural representations within distributed regions involved in cognitive control that emerged at different time-points of learning. Our results demonstrate that learners’ neural systems are flexible and show distinct spatiotemporal patterns that are not dimension-specific but reflect underlying category structures.

Significance

Whether it is an alarm signifying danger or the characteristics of background noise, humans are capable of rapid auditory learning. Extant models posit that novel auditory representations emerge in the superior temporal gyrus, a region specialized for extracting behaviorally relevant auditory dimensions and transformed onto decisions via the dorsal auditory stream. Using a computational cognitive neuroscience approach, we offer an alternative viewpoint: emergent auditory representations are highly flexible, showing distinct spatial and temporal trajectories that reflect different category structures.
LanceOtron: a deep learning peak caller for ATAC-seq, ChIP-seq, and DNase-seq
Authors: Hentges Lance D. , Sergeant Martin J. , Downes Damien J. , Hughes Jim R. , Taylor Stephen
Published: January 2021

ATAC-seq, ChIP-seq, and DNase-seq have revolutionized molecular biology by allowing researchers to identify important DNA-encoded elements genome-wide. Regions where these elements are found appear as peaks in the analog signal of an assay’s coverage track, and despite the ease with which humans can visually categorize these regions, meaningful peak calls from whole genome datasets require complex analytical techniques. Current methods focus on statistical tests to classify peaks, reducing the information-dense peak shapes to simply maximum height, and discounting that background signals do not completely follow any known probability distribution for significance testing. Deep learning has been shown to be highly accurate for image recognition, on par or exceeding human ability, providing an opportunity to reimagine and improve peak calling. We present the peak calling framework LanceOtron, which combines multifaceted enrichment measurements with deep learning image recognition techniques for assessing peak shape. In benchmarking transcription factor binding, chromatin modification, and open chromatin datasets, LanceOtron outperforms the long-standing, gold-standard peak caller MACS2 through its improved selectivity and near perfect sensitivity. In addition to command line accessibility, a graphical web application was designed to give any researcher the ability to generate optimal peak calls and interactive visualizations in a single step.
Endometrial Gap Junction Expression - Early Indicators of Endometriosis and Integral to Invasiveness
Authors: Chen Chen-Wei , Chavez Jeffery , Lin Li-Ling , Wang Chiou-Miin , Hsu Ya-Ting , Hart Matthew J. , Ruan Jianhua , Gillette Laurel , Burney Richard O. , Schenken Robert S. , Robinson Randal D. , Gaczynska Maria , Osmulski Pawel , Kirma Nameer B. , Nicholson Bruce J.
Published: January 2021

Endometriosis is an invasive disease, and a leading cause of pain, infertility and disability among women, with an incidence 10 fold that of cancer. A more complete understanding of disease pathogenesis is essential for the development of non-surgical diagnostic assays and non-hormonal therapeutics. Avoidance of immune clearance and implantation of endometrial tissue on peritoneal surfaces are features of endometriosis lesion formation that overlap with cancer metastasis. Connexins, and the gap junctions they form, have been implicated in cancer progression, and may be associated endometriosis pathophysiology. Single cell transcriptomic profiling of endometrial epithelial and stromal cells from women with endometriosis reveals a striking and progressive shift in expression of connexins and related regulatory and junctional genes. We demonstrate that gap junction coupling between endometrial cells and the peritoneal mesothelium is dramatically induced, specifically in endometriosis patients, and is required for invasion by inducing breakdown of the mesothelial barrier function.
Meningeal dendritic cells-astrocytes interactions elevate the kynurenine metabolic pathway to sustain neuropathic pain
Authors: Maganin Alexandre G. , Souza Guilherme R. , Fonseca Miriam D. , Lopes Alexandre H. , Guimarães Rafaela M. , Dagostin André , Cecilio Nerry T. , Mendes Atlante S. , Gomes Francisco I. , Marques Lucas M. , Silva Rangel L , Arruda Leticia M. , Santana Denis A. , Lemos Henrique , Huang Lei , Davoli-Ferreira Marcela , Coelho Danielle S. , Sant’anna Morena B. , Kusuda Ricardo , Talbot Jhimmy , Pacholczyk Gabriela , Buqui Gabriela A. , Lopes Norberto P. , Alves-Filho Jose C. , Leão Ricardo , O’Connor Jason C. , Cunha Fernando Q. , Mellor Andrew , Cunha Thiago M.
Published: January 2021

Neuropathic pain is triggered by injury to the somatosensory system, and is one of the most important types of chronic pain. Nevertheless, critical pathophysiological mechanisms that maintain neuropathic pain are poorly understood. Here, we show that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase (IDO) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO upregulation in dendritic cells that accumulate in the dorsal root leptomeninges led to increased levels of kynurenine (Kyn) in the spinal cord, where Kyn is metabolized by astrocytes-expressed kynurenine-3-monooxygenase into a pro-nociceptive metabolite 3-hydroxykynurenine. In conclusion, these data reveal a novel role for KYNPATH as an important factor maintaining neuropathic pain during neuroimmune-glia cells interactions. This novel paradigm offers potential new targets for drug development against this type of chronic pain.
Inhalable textile microplastic fibers impair lung repair
Authors: van Dijk F. , Song S. , van Eck G.W.A , Wu X. , Bos I.S.T. , Boom D.H.A. , Kooter I.M. , Spierings D.C.J. , Wardenaar R. , Cole M. , Salvati A. , Gosens R. , Melgert B.N.
Published: January 2021

Synthetic textiles shed fibers that accumulate indoors and this results in continuous exposure when indoors. High exposure to microplastic fibers in nylon flock workers has been linked to the development of airway and interstitial lung disease, but the exact health effects of microplastic fibers on the lungs are unknown. Here we determined effects of polyester and nylon textile microplastic fibers on airway and alveolar epithelial cells using human and murine lung organoids. We observed that particularly nylon microfibers had a negative impact on the growth and development of airway organoids. We demonstrated that this effect was mediated by components leaking from nylon. Moreover, our data suggested that microplastic textile fibers may especially harm the developing airways or airways undergoing repair. Our results call for a need to assess exposure and inhalation levels in indoor environments to accurately determine the actual risk of these fibers to human health.

Teaser

Airborne fibers shed from synthetic textiles, in particular nylon, can inhibit repair of the cells coating the airways
TREM2is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor
Authors: Ferrara Skylar J. , Chaudhary Priya , DeBell Margaret J. , Marracci Gail , Miller Hannah , Calkins Evan , Pocius Edvinas , Napier Brooke A. , Emery Ben , Bourdette Dennis , Scanlan Thomas S.
Published: January 2021

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. We report here thatTREM2is a thyroid hormone regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone. Both endogenous thyroid hormone and sobetirome, a synthetic thyroid hormone agonist drug, suppress pro-inflammatory cytokine production from myeloid cells including macrophages that have been treated with the SARS-CoV-2 spike protein which produces a strong, pro-inflammatory phenotype. Thyroid hormone agonism was also found to induce phagocytic behavior in microglia, a phenotype consistent with activation of the TREM2 pathway. The thyroid hormone antagonist NH-3 blocks the anti-inflammatory effects of thyroid hormone agonists and suppresses microglia phagocytosis. Finally, in a murine experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model, treatment with Sob-AM2, a CNS-penetrating sobetirome prodrug, results in increasedTrem2expression in disease lesion resident myeloid cells which correlates with therapeutic benefit in the EAE clinical score and reduced damage to myelin. Our findings represent the first report of endocrine regulation ofTREM2and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small molecule therapeutic agents.
Estimating the fundamental niche: accounting for the uneven availability of existing climates in the calibration area
Authors: Jiménez L. , Soberón J.
Published: January 2021

Studies that question important conceptual and methodological aspects of the field of ecological niche modeling (and species distribution modeling) have cast doubts on whether it is possible to estimate the fundamental niche of a species using presence-only data. The main limitation in niche estimation is that presence data come from the realized niche, which is only a subset of the fundamental niche. Most of the existing methods lack the ability to overcome this limitation and therefore fit niches that resemble the realized niche. To obtain a more accurate estimate of the fundamental niche, we propose using the geographic region that is accessible to a species (based on its dispersal ability) to determine a sampling distribution, in environmental space, from which we can quantify the likelihood of observing a particular environmental combination in a sample of presence points. We incorporate this sampling distribution into a multivariate normal model (i.e., a Mahalanobis distance model) by creating a weight function that modifies the probabilities of observing different environmental combinations in a sample of presences. This modification accounts for the uneven availability of environmental conditions. We show that the parameters of this weighted-normal model can be approximated with a maximum likelihood estimation approach; and then used to draw ellipsoids (confidence regions) that represent the fundamental niche of the species. We illustrate the application of our model with two worked examples. First, we use presence data for an invasive species and an accessible area that includes only its native range to evaluate whether the fitted model predicts confirmed establishments of the species outside its native range. Second, we use presence data for closely related species with known accessible areas to demonstrate how the different dispersal abilities of the species constrain a classic Mahalanobis distance model. Overall, we show that accounting for the distribution of environmental conditions that are accessible to a species indeed affects the estimation of the ellipsoids used to model its fundamental niche.
Can we put Humpty Dumpty back together again? What does protein quantification mean in bottom-up proteomics?
Authors: Plubell Deanna L. , Käll Lukas , Webb-Robertson Bobbie-Jo , Bramer Lisa , Ives Ashley , Kelleher Neil L. , Smith Lloyd M. , Montine Thomas J. , Wu Christine C. , MacCoss Michael J.
Published: January 2021

Bottom-up proteomics provides peptide measurements and has been invaluable for moving proteomics into large-scale analyses. In bottom-up proteomics, protein parsimony and protein inference derived from these measured peptides are important for determining which protein coding genes are present. However, given the complexity of RNA splicing processes, and how proteins can be modified post-translationally, it is overly simplistic to assume that all peptides that map to a singular protein coding gene will demonstrate the same quantitative response. Accordingly, by assuming all peptides from a protein coding sequence are representative of the same protein we may be missing out on detecting important biological differences. To better account for the complexity of the proteome we need to think of new or better ways of handling peptide data.
INTEGRATION OF ENGINEERED “SPARK-CELL” SPHEROIDS FOR OPTICAL PACING OF CARDIAC TISSUE
Authors: Chua Christianne , Han Julie , Li Weizhen , Liu Wei , Entcheva Emilia
Published: January 2021

Optogenetic methods for pacing of cardiac tissue can be realized by direct genetic modification of the cardiomyocytes to express light-sensitive actuators, such as channelrhodopsin-2, ChR2, or by introduction of light-sensitized non-myocytes that couple to the cardiac cells and yield responsiveness to optical pacing. In this study, we engineer three-dimensional “spark cells” spheroids, composed of ChR2-expressing human embryonic kidney cells, and characterize their morphology as function of cell density and time. These “spark-cell” spheroids are then deployed to demonstrate site-specific optical pacing of human stem-cell-derived cardiomyocytes (hiPSC-CMs) in 96-well format using non-localized light application and all-optical electrophysiology. We show that the spheroids can be handled using liquid pipetting and can confer optical responsiveness of cardiac tissue earlier than direct viral or liposomal genetic modification of the cardiomyocytes, with 24% providing reliable stimulation of the iPSC-CMs within 6 hours and >80% within 24 hours. Our results demonstrate a scalable, cost-effective method to achieve contactless optical stimulation of cardiac cell constructs that can be integrated in a robotics-amenable workflow for high-throughput drug testing.

GRAPHICAL ABSTRACT
Antifungal effects of alantolactone onCandida albicans:anin vitrostudy
Authors: Liu Xin , Zhong Lili , Ma Zhiming , Sui Yujie , Xie Jia’nan , Ma Tonghui , Yang Longfei
Published: January 2021

The human fungal pathogenCandida albicanscan cause many kinds of infections, including biofilm infections on medical devices, while the available antifungal drugs are limited to only a few. In this study, alantolactone (Ala) demonstrated antifungal activities againstC. albicans, as well as otherCandidaspecies, with a MIC of 72 μg/mL. Ala could also inhibit the adhesion, yeast-to-hyphal transition, biofilm formation and development ofC. albicans. The exopolysaccharide of biofilm matrix and extracellular phospholipase production could also be reduced by Ala treatment. Ala could increase permeability ofC. albicanscell membrane and ROS contribute to the antifungal activity of Ala. Overall, the present study suggests that Ala may provide a promising candidate for developing antifungal drugs againstC. albicansinfections.
Specificity and selective advantage of an exclusion system in the integrative and conjugative element ICEBs1ofBacillus subtilis
Authors: Davis Kathleen P. , Grossman Alan D.
Published: January 2021

Integrative and conjugative elements (ICEs) are mobile genetic elements capable of transferring their own and other DNA. They contribute to the spread of antibiotic resistances and other important traits for bacterial evolution. Exclusion is a mechanism used by many conjugative plasmids and a few ICEs to prevent their host cell from acquiring a second copy of the cognate element. ICEBs1ofBacillus subtilishas an exclusion mechanism whereby the exclusion protein YddJ in a potential recipient inhibits the activity of the ICEBs1-encoded conjugation machinery in a potential donor. The target of YddJ-mediated exclusion is the conjugation protein ConG (a VirB6 homolog). Here we defined the regions of YddJ and ConG that confer exclusion specificity and determined the importance of exclusion to host cells. Using chimeras that had parts of ConG from ICEBs1and the closely related ICEBat1we identified a putative extracellular loop of ConG that conferred specificity for exclusion by the cognate YddJ. Using chimeras of YddJ from ICEBs1and ICEBat1we identified two regions in YddJ needed for exclusion specificity. We also found that YddJ-mediated exclusion reduced death of donor cells following conjugation into recipients. Donor death was dependent on the ability of transconjugants to themselves become donors and was reduced under osmo-protective conditions, indicating that death was likely due to alterations in the donor cell envelope caused by excessive conjugation. We postulate that elements that can have high frequencies of transfer likely evolved exclusion mechanisms to protect the host cells from excessive death.

Importance

Horizontal gene transfer is a driving force in bacterial evolution, responsible for the spread of many traits, including antibiotic and heavy metal resistances. Conjugation, one type of horizontal gene transfer, involves DNA transfer from donor to recipient cells through conjugation machinery and direct cell-cell contact. Exclusion mechanisms allow conjugative elements to prevent their host from acquiring additional copies of the element, and are highly specific enabling hosts to acquire heterologous elements. We defined regions of the exclusion protein and its target in the conjugation machinery that convey high specificity of exclusion. We found that exclusion protects donors from cell death during periods of high transfer. This is likely important for the element to enter new populations of cells.
The King’s College London Coronavirus Health and Experiences of Colleagues at King’s Study: SARS-CoV-2 antibody response in a higher education sample
Authors: Leightley Daniel , Vitiello Valentina , Wickersham Alice , Davis Katrina A.S. , Bergin-Cartwright Gabriella , Lavelle Grace , Stevelink Sharon A.M , Hotopf Matthew , Razavi Reza
Published: January 2021

Objective

To assess the feasibility of home antibody testing as part of large-scale study, the King’s College London Coronavirus Health and Experiences of Colleagues at King’s (KCL CHECK).

Methods

Participants of the KCL CHECK study were sent a SureScreen Diagnostics COVID-19 IgG/IgM Rapid Test Cassette to complete at home in June 2020 (phase 1) and September 2020 (phase 2). Participants were asked to upload a test result image to a study website. Test result images and sociodemographic information were analysed by the research team.

Results

A total of n=2716 participants enrolled in the KCL CHECK study, with n=2003 (73.7%) and n=1825 (69.3%) consenting and responding to phase 1 and 2. Of these, n=1882 (93.9%; phase 1) and n=1675 (91.8%; phase 2) returned a valid result. n=123 (6.5%; phase 1) and n=91 (5.4%; phase 2) tested positive for SARS-CoV-2 antibodies. A total of n=1488 participants provided a result in both phases, with n=57 (3.8%) testing positive for SARS- CoV-2 antibodies across both phases, suggesting a reduction in the number of positive antibody results over time. Initial comparisons showed variation by age group, gender and clinical role.

Conclusions

Our study highlights the feasibility of rapid, repeated and low-cost SARS-CoV-2 serological testing without the need for face-to-face contact.

What is already known about this subject?

Higher education institutions have a duty of care to minimise the spread and transmission of COVID-19 in its campuses, and among staff and students. The reopening of higher education buildings and campuses has brought about a mass movement of students, academics and support staff from across the UK. Serological antibody studies can assist by highlighting groups of people and behaviours associated with high risk of COVID-19.

What are the new findings?

We report a framework for SARS-CoV-2 serological antibody testing in an occupational group of postgraduate research students and current members of staff at King’s College London. Over two phases of data collection, 6.5% (phase 1) and 5.4% (phase 2) tested positive for SARS-CoV-2 antibodies, with only 3.8% testing positive for antibodies in both phases, suggesting a reduction in positive antibody results over time.

How might this impact on policy or clinical practice in the foreseeable future?

Our study highlights the feasibility of rapidly deploying low-cost and repeatable SARS-CoV-2 serological testing, without the need for face-to-face contact, to support the higher education system of the UK.
Public Views about COVID-19 “Immunity Passports”
Authors: Hall Mark A. , Studdert David M.
Published: January 2021

Importance

Discovery of effective vaccines and increased confidence that infection confers extended protection against COVID-19 have renewed discussion of using immunity certificates or “passports” to selectively reduce ongoing public health restrictions.

Objective

To determine public views regarding government and private conferral of immunity privileges.

Design and Setting

National on-line survey fielded in June 2020. Participants were randomly asked about either government “passports” or private “certificates” for COVID-19 immunity.

Participants

Adults from a standing panel maintained for academic research, selected to approximate national demographics.

Main Outcomes/Measures

Level of support/opposition to immunity privileges, and whether views vary based on: government vs. private adoption; demographics; political affiliation or views; or various COVID19-related attitudes and experiences.

Results

Of 1315 respondents, 45.2% supported immunity privileges, with slightly more favoring private certificates than government passports (48.1% vs 42.6%, p=0.04). Support was greater for using passports or certificates to enable returns to high-risk jobs or attendance at large recreational events than for returning to work generally. Levels of support did not vary significantly according to age groups, socioeconomic or employment status, urbanicity, political affiliation or views, or whether the respondent had chronic disease(s). However, estimates from adjusted analyses showed less support among women (Odds Ratio, 0.64; 95% Confidence Interval, 0.51 to 0.80), and among Hispanics (0.56; 0.40 to 0.78) and other minorities (0.58; 0.40 to 0.85) compared with whites, but not among blacks (0.83; 0.60 to 1.15). Support was much higher among those who personally wanted a passport or certificate (75.6% vs 24.4%) and much lower among those who believed this would harm the social fabric of their community (22.9% vs 77.1%).

Conclusions and Relevance

Public views are divided on either government or private use of immunity certificates, but, prior to any efforts to politicize the issues, these views do not vary along usual political lines, nor by characteristics that indicate individual vulnerability to infection. Social consensus on the desirability of an immunity privileges programs may be difficult to achieve.

Key Points

Question

What are the public’s views on government or private use of immunity “passports” to selectively lift COVID-19 restrictions?

Findings

Views are divided and do not vary substantially according to political affiliation or many demographic factors. Support is greater among men but lower among Hispanics and those who believe that immunity privileges would harm the social fabric of society.

Meaning

Social consensus will be difficult to achieve on the appropriateness of immunity privileges.
An Updated Investigation Prior To COVID-19 Vaccination Program In Indonesia: Full-Length Genome Mutation Analysis Of SARS-CoV-2
Authors: Nidom Reviany V. , Indrasari Setyarina , Normalina Irine , Nidom Astria N. , Afifah Balqis , Dewi Lestari , Putra Andra Kusuma , Ansori Arif N. M. , Kusala Muhammad K. J. , Alamudi Mohammad Y. , Nidom Chairul A.
Published: January 2021

Introduction

Indonesia kick-started the big project of COVID-19 vaccination program in January 2021 by employed vaccine to the president of Indonesia. The outbreak and rapid transmission of COVID-19 have endangered the global health and economy. This study aimed to investigate the full-length genome mutation analysis of 166 Indonesian SARS-CoV-2 isolates as 12 January 2021.

Methods

All data of isolates was extracted from the Global Initiative on Sharing All Influenza Data (GISAID) EpiCoV database. CoVsurver was employed to investigate the full-length genome mutation analysis of all isolates. Furthermore, this study also focused on the unlocking of mutation in Indonesian SARS-CoV-2 isolates S protein. WIV04 isolate that was originated from Wuhan, China was used as a virus reference according to CoVsurver default. All data was visualized using GraphPad Prism software, PyMOL, and BioRender.

Results

This study result showed that a full-length genome mutation analysis of 166 Indonesian SARS-CoV-2 isolates was successfully discovered. Every single mutation in S protein was described and then visualised by employing BioRender. Furthermore, it also found that D614G mutation appeared in 103 Indonesian SARS-CoV-2 isolates.

Conclusion

To sum up, this study helps to observe the spread of the COVID-19 transmission. However, it would like to propose that the epidemiological surveillance and genomics studies might be improved on COVID-19 pandemic in Indonesia.
Profiling acetogenic community dynamics in anaerobic digesters - comparative analyses using next-generation sequencing and T-RFLP
Authors: Singh Abhijeet , Müller Bettina , Schnürer Anna
Published: January 2021

Acetogens play a key role in anaerobic degradation of organic material and in maintaining biogas process efficiency. Profiling this community and its temporal changes can help evaluate process stability and function, especially under disturbance/stress conditions, and avoid complete process failure. The formyltetrahydrofolate synthetase (FTHFS) gene can be used as a marker for acetogenic community profiling in diverse environments. In this study, we developed a new high-throughput FTHFS gene sequencing method for acetogenic community profiling and compared it with conventional T-RFLP of the FTHFS gene, 16S rRNA gene-based profiling of the whole bacterial community, and indirect analysis via 16S rRNA profiling of the FTHFS gene-harbouring community. Analyses and method comparisons were made using samples from two laboratory-scale biogas processes, one operated under stable control and one exposed to controlled overloading disturbance. Comparative analysis revealed satisfactory detection of the bacterial community and its changes for all methods, but with some differences in resolution and taxonomic identification. FTHFS gene sequencing was found to be the most suitable and reliable method to study acetogenic communities. These results pave the way for community profiling in various biogas processes and in other environments where the dynamics of acetogenic bacteria have not been well studied.

GRAPHICAL ABSTRACT

ONE SENTENCE SUMMARY

Our high-throughput FTHFS gene AmpSeq method for barcoded samples and unsupervised analysis with AcetoScan accurately reveals temporal dynamics of acetogenic community structure in anaerobic digesters.
CUT&RUNTools 2.0: A pipeline for single-cell and bulk-level CUT&RUN and CUT&Tag data analysis
Authors: Yu Fulong , Sankaran Vijay G. , Yuan Guo-Cheng
Published: January 2021

Genome-wide profiling of transcription factor binding and chromatin states is a widely-used approach for mechanistic understanding of gene regulation. Recent technology development has enabled such profiling at single-cell resolution. However, an end-to-end computational pipeline for analyzing such data is still lacking. To fill this gap, we have developed a flexible pipeline for analysis and visualization of single-cell CUT&RUN and CUT&Tag data, which provides functions for sequence alignment, quality control, dimensionality reduction, cell clustering, data aggregation, and visualization. Furthermore, it is also seamlessly integrated with the functions in original CUT&RUNTools for population-level analyses. As such, this provides a valuable toolbox for the community.