bluuebunny/crossref_metadata_2025 huggingface dataset:
Different computations underlie overt and covert spatial attention
Authors: Li Hsin-Hung , Pan Jasmine , Carrasco Marisa
Published: July 2020

Perception and action are tightly coupled: visual responses at the saccade target are enhanced right before saccade onset. This phenomenon, presaccadic attention, is a form of overt attention—deployment of visual attention with concurrent eye movements. Presaccadic attention is well-documented, but its underlying computational process remains unknown. This is in stark contrast with covert attention—deployment of visual attention without concurrent eye movements—for which the computational process is well characterized. Here, a series of psychophysical experiments reveal that presaccadic attention modulates visual performance only via response gain changes even when attention field size increases, violating the predictions of a normalization model of attention, which has been widely used to explain the computations underlying covert attention. Our empirical results and model comparisons reveal that the perceptual modulations by overt and covert spatial attention are mediated through different computations.
Coupling between lipid miscibility and phosphotyrosine driven protein condensation at the membrane
Authors: Chung J. K. , Huang W. Y. C. , Carbone C. B. , Nocka L. M. , Parikh A. N. , Vale R. D. , Groves J. T.
Published: July 2020

Lipid miscibility phase separation has long been considered to be a central element of cell membrane organization. More recently, protein condensation phase transitions, into three-dimensional droplets or in two-dimensional lattices on membrane surfaces, have emerged as another important organizational principle within cells. Here, we reconstitute the LAT:Grb2:SOS protein condensation on the surface of giant unilamellar vesicles capable of undergoing lipid phase separations. Our results indicate that assembly of the protein condensate on the membrane surface can drive lipid phase separation. This phase transition occurs isothermally and is governed by tyrosine phosphorylation on LAT. Furthermore, we observe that the induced lipid phase separation drives localization of the SOS substrate, K-Ras, into the LAT:Grb2:SOS protein condensate.

Statement of Significance

Protein condensation phase transitions are emerging as an important organizing principles in cells. One such condensate plays a key role in T cell receptor signaling. Immediately after receptor activation, multivalent phosphorylation of the adaptor protein LAT at the plasma membrane leads to networked assembly of a number of signaling proteins into a two-dimensional condensate on the membrane surface. In this study, we demonstrate that LAT condensates in reconstituted vesicles are sufficient to drive lipid phase separation. This lipid reorganization drives another key downstream signaling molecule, Ras, into the LAT condensates. These results show that the LAT condensation phase transition, which is actively controlled by phosphorylation reactions, extends its influence to control lipid phase separation in the underlying membrane.
Plasticity in astrocyte subpopulations regulates heroin relapse
Authors: Kruyer Anna , Angelis Ariana , Garcia-Keller Constanza , Li Hong , Kalivas Peter W.
Published: July 2020

Opioid use disorder (OUD) produces detrimental personal and societal consequences. Astrocytes are a major cell group in the brain that receives little attention in mediating OUD. We determined how astrocytes and the astroglial glutamate transporter, GLT-1, in the nucleus accumbens core adapt and contribute to heroin seeking in rats. Seeking heroin, but not sucrose, produced two transient forms of plasticity in different astroglial subpopulations. Increased morphological proximity to synapses occurred in one subpopulation and increased extrasynaptic GLT-1 expression in another. Augmented synapse proximity by astroglia occurred selectively at D2-dopamine receptor expressing dendrites, while changes in GLT-1 were not neuron-subtype specific. Importantly, mRNA-antisense inhibition of either morphological or GLT-1 plasticity promoted cue-induced heroin seeking. We show that heroin cues induce two distinct forms of transient plasticity in separate astroglial subpopulations that dampen heroin relapse.

TEASER

Different subpopulations of astrocytes engage with accumbens synapses to dampen heroin relapse.
ERRα coordinates actin and focal adhesion dynamics
Authors: Tribollet Violaine , Cerutti Catherine , Géloën Alain , Danty-Berger Emmanuelle , De Mets Richard , Balland Martial , Courchet Julien , Vanacker Jean-Marc , Forcet Christelle
Published: July 2020

Cell migration depends on the dynamic organization of the actin cytoskeleton and assembly and disassembly of focal adhesions (FA). However the precise mechanisms coordinating these processes remain poorly understood. We previously identified the estrogen-related receptor α (ERRα) as a major regulator of cell migration. Here, we show that loss of ERRα leads to abnormal accumulation of actin filaments that is associated with an increase in the level of inactive form of the actin-depolymerizing factor cofilin. We further show that ERRα depletion decreases cell adhesion and promotes defective FA formation and turnover. Interestingly, specific inhibition of the RhoA-ROCK-LIMK-cofilin pathway rescues the actin polymerization defects resulting from ERRα silencing, but not cell adhesion. Instead we found that MAP4K4 is a direct target of ERRα and down-regulation of its activity rescues cell adhesion and FA formation in the ERRα-depleted cells. Altogether, our results highlight a crucial role of ERRα in coordinating the dynamic of actin network and focal adhesion through the independent regulation of the RhoA and MAP4K4 pathways.
Spatial phylogenetics of butterflies in relation to environmental drivers and angiosperm diversity across North America
Authors: Earl Chandra , Belitz Michael W. , Laffan Shawn W. , Barve Vijay , Barve Narayani , Soltis Douglas E. , Allen Julie M. , Soltis Pamela S. , Mishler Brent D. , Kawahara Akito Y. , Guralnick Robert
Published: July 2020

Broad-scale quantitative assessments of biodiversity and the factors shaping it remain particularly poorly explored in insects. Here, we undertook a spatial phylogenetic analysis of North American butterflies via assembly of a time-calibrated phylogeny of the region coupled with a unique, complete range assessment for ~75% of the known species. We utilized a suite of phylodiversity metrics and associated environmental data to test whether climate stability and temperature gradients have shaped North American butterfly phylogenetic diversity and endemism. We also undertook the first direct, quantitative comparisons of spatial phylogenetic patterns between butterflies and flowering plants in North America. We expected concordance between butterflies and angiosperms based on both shared historical environmental drivers and presumed strong butterfly-host plant specializations. We instead found that biodiversity patterns in butterflies are strikingly different from flowering plants in some regions of the continent. In particular, the warm desert regions of the southwestern United States and Mexico showed surprisingly high butterfly phylogenetic diversity and endemism, in contrast to much lower values for angiosperms. Butterflies did not show patterns of phylogenetic clustering as found in flowering plants, suggesting differences in habitat conservation between the two groups. Finally, we found weak relationships and spatially structured biases in relative branching timing between angiosperms and butterflies. These results suggest that shared biogeographic histories and trophic associations do not necessarily assure similar diversity outcomes. The work has applied value in conservation planning, documenting warm deserts as an important North American butterfly biodiversity hotspot.
Sister chromatid repair maintains genomic integrity during meiosis inCaenorhabditis elegans
Authors: Toraason Erik , Clark Cordell , Horacek Anna , Glover Marissa L. , Salagean Alina , Libuda Diana E.
Published: July 2020

During meiosis, the maintenance of genome integrity is critical for generating viable haploid gametes [1]. In meiotic prophase I, double-strand DNA breaks (DSBs) are induced and a subset of these DSBs are repaired as interhomolog crossovers to ensure proper chromosome segregation. DSBs in excess of the permitted number of crossovers must be repaired by other pathways to ensure genome integrity [2]. To determine if the sister chromatid is engaged for meiotic DSB repair during oogenesis, we developed an assay to detect sister chromatid repair events at a defined DSB site duringCaenorhabditis elegansmeiosis. Using this assay, we directly demonstrate that the sister chromatid is available as a meiotic repair template for both crossover and noncrossover recombination, with noncrossovers being the predominant recombination outcome. We additionally find that the sister chromatid is the exclusive recombination partner for DSBs during late meiotic prophase I. Analysis of noncrossover conversion tract sequences reveals that DSBs are processed similarly throughout prophase I and recombination intermediates remain central around the DSB site. Further, we demonstrate that the SMC-5/6 complex is required for long conversion tracts in early prophase I and intersister crossovers during late meiotic prophase I; whereas, the XPF-1 nuclease is required only in late prophase to promote sister chromatid repair. In response to exogenous DNA damage at different stages of meiosis, we find that mutants for SMC-5/6 and XPF-1 have differential effects on progeny viability. Overall, we propose that SMC-5/6 both processes recombination intermediates and promotes sister chromatid repair within meiotic prophase I, while XPF-1 is required as an intersister resolvase only in late prophase I.
MicrobeTrace: Retooling Molecular Epidemiology for Rapid Public Health Response
Authors: Campbell Ellsworth M. , Boyles Anthony , Shankar Anupama , Kim Jay , Knyazev Sergey , Switzer William M.
Published: July 2020

Motivation

Outbreak investigations use data from interviews, healthcare providers, laboratories and surveillance systems. However, integrated use of data from multiple sources requires a patchwork of software that present challenges in usability, interoperability, confidentiality, and cost. Rapid integration, visualization and analysis of data from multiple sources can guide effective public health interventions.

Results

We developed MicrobeTrace to facilitate rapid public health responses by overcoming barriers to data integration and exploration in molecular epidemiology. Using publicly available HIV sequences and other data, we demonstrate the analysis of viral genetic distance networks and introduce a novel approach to minimum spanning trees that simplifies results. We also illustrate the potential utility of MicrobeTrace in support of contact tracing by analyzing and displaying data from an outbreak of SARS-CoV-2 in South Korea in early 2020.

Availability and Implementation

MicrobeTrace is a web-based, client-side, JavaScript application (https://microbetrace.cdc.gov) that runs in Chromium-based browsers and remains fully-operational without an internet connection. MicrobeTrace is developed and actively maintained by the Centers for Disease Control and Prevention. The source code is available athttps://github.com/cdcgov/microbetrace.

Contact

ells@cdc.gov
Environmental DNA metabarcoding provides enhanced detection of the European eelAnguilla anguillaand fish community structure in pumped river catchments
Authors: Griffiths Nathan P. , Bolland Jonathan D. , Wright Rosalind M. , Murphy Leona A. , Donnelly Robert K. , Watson Hayley V. , Hänfling Bernd
Published: July 2020

The European eelAnguilla anguilla(eel hereafter) is critically endangered and has a catadromous lifecycle, which means adult eels that live in pumped catchments must pass through pumps during their downstream spawning migration. We are currently lacking detailed site-by-site eel distribution information in order to estimate the overall impact of individual pumping stations on eel escapement, and as such lack the data to enable informed prioritisation of pumping station management and targeted mitigation. In this study, we investigated whether environmental DNA (eDNA) metabarcoding can provide increased detection sensitivity for eel and fish community structure in highly regulated pumped catchments, when compared directly to current standard practice fish survey protocols (seine netting/electric fishing). Eels were detected in 14/17 sites (82.4%) using eDNA metabarcoding in contrast to 3/17 (17.6%) using traditional catch methods. Additionally, when using eDNA monitoring species richness was higher in 16/17 sites (94.1%) and site occupancy ≥ traditional methods for 23/26 of the fish species detected (88.5%). While eDNA methods presented significantly higher average species richness and species site occupancy overall, eDNA and Catch methods were positively correlated in terms of species richness and site occupancy. We therefore found that eDNA metabarcoding was a high sensitivity method for detecting eels in pumped catchments, while also increasing the detection of overall fish community structure compared to traditional catch methods. In addition, we highlight how eDNA monitoring is especially suited to increased detection of particular species, with traditional methods sufficient for others. This high sensitivity, coupled with the ability to sample multiple sites in a short time frame suggests eDNA metabarcoding could be an invaluable tool when prioritising pumping station management.
Rapidin vitroassays for screening neutralizing antibodies and antivirals against SARS-CoV-2
Authors: Park Jun-Gyu , Oladduni Fatai S. , Chiem Kevin , Ye Chengjin , Pipenbrink Michael , Moran Thomas , Walter Mark R. , Kobie James , Martinez-Sobrido Luis
Published: July 2020

Towards the end of 2019, a novel coronavirus (CoV) named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), genetically similar to severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1), emerged in Wuhan, Hubei province of China, and has been responsible of coronavirus disease 2019 (COVID-19) in humans. Since its first report, SARS-CoV-2 has resulted in a global pandemic, with over 10 million human infections and over 560,000 deaths reported worldwide at the end of June 2020. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines and/or antivirals licensed against SARS-CoV-2, and the high economical and health impact of SARS-CoV-2 has placed global pressure on the scientific community to identify effective prophylactic and therapeutic treatments for the treatment of SARS-CoV-2 infection and associated COVID-19 disease. While some compounds have been already reported to reduce SARS-CoV-2 infection and a handful of monoclonal antibodies (mAbs) have been described that neutralize SARS-CoV-2, there is an urgent need for the development and standardization of assays which can be used in high through-put screening (HTS) settings to identify new antivirals and/or neutralizing mAbs against SARS-CoV-2. Here, we described a rapid, accurate and highly reproducible plaque reduction microneutralization (PRMNT) assay that can be quickly adapted for the identification and characterization of both neutralizing mAbs and antivirals against SARS-CoV-2. Importantly, our MNA is compatible with HTS settings to interrogate large and/or complex libraries of mAbs and/or antivirals to identify those with neutralizing and/or antiviral activity, respectively, against SARS-CoV-2.
Brain hierarchy score: Which deep neural networks are hierarchically brain-like?
Authors: Nonaka Soma , Majima Kei , Aoki Shuntaro C. , Kamitani Yukiyasu
Published: July 2020

Achievement of human-level image recognition by deep neural networks (DNNs) has spurred interest in whether and how DNNs are brain-like. Both DNNs and the visual cortex perform hierarchical processing, and correspondence has been shown between hierarchical visual areas and DNN layers in representing visual features. Here, we propose the brain hierarchy (BH) score as a metric to quantify the degree of hierarchical correspondence based on the decoding of individual DNN unit activations from human brain activity. We find that BH scores for 29 pretrained DNNs with varying architectures are negatively correlated with image recognition performance, indicating that recently developed high-performance DNNs are not necessarily brain-like. Experimental manipulations of DNN models suggest that relatively simple feedforward architecture with broad spatial integration is critical to brain-like hierarchy. Our method provides new ways for designing DNNs and understanding the brain in consideration of their representational homology.
Incoherent feedforward regulation via Sox9 and Erk underpins mouse tracheal cartilage development
Authors: Yoshida Takuya , Matsuda Michiyuki , Hirashima Tsuyoshi
Published: July 2020

Tracheal cartilage provides architectural integrity to the respiratory airway, and defects in this structure during embryonic development cause severe congenital anomalies. Previous genetic studies have revealed genes that are critical for the development of tracheal cartilage. However, it is still unclear how crosstalk between these proteins regulates tracheal cartilage formation. Here we show a core regulatory network underlying murine tracheal chondrogenesis from embryonic day (E) 12.5 to E15.5, by combining volumetric imaging of fluorescence reporters, inhibitor assays, and mathematical modeling. We focused on SRY-box transcription factor 9 (Sox9) and extracellular signal-regulated kinase (Erk) in the tracheal mesenchyme, and observed a synchronous, inverted U-shaped temporal change in both Sox9 expression and Erk activity with a peak at E14.5, whereas the expression level of downstream cartilage matrix genes, such as collagen II alpha 1 (Col2a1) and aggrecan (Agc1), monotonically increased. Inhibitor assays revealed that the Erk signaling pathway functions as an inhibitory regulator of tracheal cartilage differentiation during this period. These results suggest that expression of the cartilage matrix genes is controlled by an incoherent feedforward loop via Sox9 and Erk, which is supported by a mathematical model. Furthermore, the modeling analysis suggests that a Sox9-Erk incoherent feedforward regulation augment the robustness against the variation of upstream factors. The present study provides a better understanding of the regulatory network underlying the tracheal development and will be helpful for efficient induction of tracheal organoids.
Detection of clustered anomalies in single-voxel morphometry as a rapid automated method for identifying intracranial aneurysms
Authors: Allenby Mark C , Liang Ee Shern , Harvey James , Woodruff Maria A , Prior Marita , Winter Craig D , Alonso-Caneiro David
Published: July 2020

Unruptured intracranial aneurysms (UIAs) are prevalent neurovascular anomalies which, in rare circumstances, rupture to create a catastrophic subarachnoid haemorrhage. Although surgical management can reduce rupture risk, the majority of IAs exist undiscovered until rupture. Current computer-aided UIA diagnoses sensitively detect and measure UIAs within cranial angiograms, but remain limited to low specificities whose output requires considerable neuroradiologist interpretation not amenable to broad screening efforts. To address these limitations, we propose an analysis which interprets single-voxel morphometry of segmented neurovasculature to identify UIAs. Once neurovascular anatomy of a specified resolution is segmented, interrelationships between voxel-specific morphometries are estimated and spatially-clustered outliers are identified as UIA candidates. Our automated solution detects UIAs within magnetic resonance angiograms (MRA) at unmatched 86% specificity and 81% sensitivity using 3 minutes on a conventional laptop. Our approach does not rely on interpatient comparisons or training datasets which could be difficult to amass and process for rare incidentally discovered UIAs within large MRA files, and in doing so, is versatile to user-defined segmentation quality, to detection sensitivity, and across a range of imaging resolutions and modalities. We propose this method as a unique tool to aid UIA screening, characterisation of abnormal vasculature in at-risk patients, morphometry-based rupture risk prediction, and identification of other vascular abnormalities.

Graphical Abstract

Highlights

Rapid and automated detection of unruptured intracranial aneurysms (UIAs) in MRAs

Highly specific, sensitive UIA detection to reduce radiologist input for screening

Detection is versatile to image resolution, modality and has tuneable mm sensitivity
COVID-19 Intensive Care Admissions Have Twice the Corrected Mortality of non-COVID-19 Viral Pneumonia
Authors: Nicolau Dan V. , Hasson Alexander
Published: July 2020

Studying the ICNARC Case Mix Programme Database has yielded results showing intensive care admissions by those infected with COVID-19 have twice the corrected mortality of patients presenting with non-COVID-19 viral pneumonia. A basis of an APACHE-II-like score denoted as “BASCA” is also outlined in this study.
Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder
Authors: Yao Shi , Ding Jing-Miao , Wu Hao , Hao Ruo-Han , Rong Yu , Ke Xin , Guo Jing , Dong Shan-Shan , Guo Yan
Published: July 2020

Bipolar disorder (BD) is a highly heritable neuropsychiatric disorder characterized by recurrent episodes of depression and mania. Since the signals identified by genome-wide association study (GWAS) often reside in the non-coding regions, understanding the biological relevance of these genetic loci has proven to be complicated. Transcriptome-wide association studies (TWAS) providing a powerful approach to identify novel disease risk genes and uncover possible causal genes at loci identified previously by GWAS. However, these methods did not consider the importance of epigenetic regulation in gene expression. Here, we developed a novel epigenetic element-based transcriptome-wide association study (ETWAS) that tests the effects of genetic variants on gene expression levels with the epigenetic features as prior and further mediates the association between predicted expression and BD. We conducted an ETWAS consisting of 20,352 cases and 31,358 controls and identified 44 transcriptome-wide significant hits. We found 14 conditionally independent genes, and 11 did not previously implicate with BD, which regarded as novel candidate genes, such asASB16in the cerebellar hemisphere (P= 9.29×10−8). We demonstrated that several genome-wide significant signals from the BD GWAS driven by genetically regulated expression, and conditioning ofNEK4explaining 90.1% of the GWAS signal. Additionally, ETWAS identified genes could explain heritability beyond that explained by GWAS-associated SNPs (P= 0.019). In conclusion, ETWAS is a powerful method, and we identified several novel candidate genes associated with BD.
High variation expected in the pace and burden of SARS-CoV-2 outbreaks across sub-Saharan Africa
Authors: Rice Benjamin L. , Annapragada Akshaya , Baker Rachel E. , Bruijning Marjolein , Dotse-Gborgbortsi Winfred , Mensah Keitly , Miller Ian F. , Motaze Nkengafac Villyen , Raherinandrasana Antso , Rajeev Malavika , Rakotonirina Julio , Ramiadantsoa Tanjona , Rasambainarivo Fidisoa , Yu Weiyu , Grenfell Bryan T. , Tatem Andrew J. , Metcalf C. Jessica E.
Published: July 2020

A surprising feature of the SARS-CoV-2 pandemic to date is the low burdens reported in sub-Saharan Africa (SSA) countries relative to other global regions. Potential explanations (e.g., warmer environments1, younger populations2–4) have yet to be framed within a comprehensive analysis accounting for factors that may offset the effects of climate and demography. Here, we synthesize factors hypothesized to shape the pace of this pandemic and its burden as it moves across SSA, encompassing demographic, comorbidity, climatic, healthcare and intervention capacity, and human mobility dimensions of risk. We find large scale diversity in probable drivers, such that outcomes are likely to be highly variable among SSA countries. While simulation shows that extensive climatic variation among SSA population centers has little effect on early outbreak trajectories, heterogeneity in connectivity is likely to play a large role in shaping the pace of viral spread. The prolonged, asynchronous outbreaks expected in weakly connected settings may result in extended stress to health systems. In addition, the observed variability in comorbidities and access to care will likely modulate the severity of infection: We show that even small shifts in the infection fatality ratio towards younger ages, which are likely in high risk settings, can eliminate the protective effect of younger populations. We highlight countries with elevated risk of ‘slow pace’, high burden outbreaks. Empirical data on the spatial extent of outbreaks within SSA countries, their patterns in severity over age, and the relationship between epidemic pace and health system disruptions are urgently needed to guide efforts to mitigate the high burden scenarios explored here.
SARS-CoV-2 receptor Angiotensin I-Converting Enzyme type 2 (ACE2) is expressed in human pancreatic β-cells and in the human pancreas microvasculature
Authors: Fignani Daniela , Licata Giada , Brusco Noemi , Nigi Laura , Grieco Giuseppina E. , Marselli Lorella , Overbergh Lut , Gysemans Conny , Colli Maikel L. , Marchetti Piero , Mathieu Chantal , Eizirik Decio L. , Sebastiani Guido , Dotta Francesco
Published: July 2020

Increasing evidence demonstrated that the expression of Angiotensin I-Converting Enzyme type 2 (ACE2), is a necessary step for SARS-CoV-2 infection permissiveness. In the light of the recent data highlighting an association between COVID-19 and diabetes, a detailed analysis aimed at evaluating ACE2 expression pattern distribution in human pancreas is still lacking. Here, we took advantage of INNODIA network EUnPOD biobank collection to thoroughly analyse ACE2, both at mRNA and protein level, in multiple human pancreatic tissues and using several methodologies.

Using multiple reagents and antibodies, we showed that ACE2 is expressed in human pancreatic islets, where it is preferentially expressed in subsets of insulin producing β-cells. ACE2 is also is highly expressed in pancreas microvasculature pericytes and moderately expressed in rare scattered ductal cells. By using different ACE2 antibodies we showed that a recently described short-ACE2 isoform is also prevalently expressed in human β-cells.

Finally, using RT-qPCR, RNA-seq and High-Content imaging screening analysis, we demonstrated that pro-inflammatory cytokines, but not palmitate, increases ACE2 expression in the β-cell line EndoC-βH1 and in primary human pancreatic islets.

Taken together, our data indicate a potential link between SARS-CoV-2 and diabetes through putative infection of pancreatic microvasculature and/or ductal cells and/or through direct β-cell virus tropism.
Single-dose intranasal vaccination elicits systemic and mucosal immunity against SARS-CoV-2
Authors: An Xingyue , Martinez-Paniagua Melisa , Rezvan Ali , Fathi Mohsen , Singh Shailbala , Biswas Sujit , Pourpak Melissa , Yee Cassian , Liu Xinli , Varadarajan Navin
Published: July 2020

A safe and durable vaccine is urgently needed to tackle the COVID19 pandemic that has infected >15 million people and caused >620,000 deaths worldwide. As with other respiratory pathogens, the nasal compartment is the first barrier that needs to be breached by the SARS-CoV-2 virus before dissemination to the lung. Despite progress at remarkable speed, current intramuscular vaccines are designed to elicit systemic immunity without conferring mucosal immunity. We report the development of an intranasal subunit vaccine that contains the trimeric or monomeric spike protein and liposomal STING agonist as adjuvant. This vaccine induces systemic neutralizing antibodies, mucosal IgA responses in the lung and nasal compartments, and T-cell responses in the lung of mice. Single-cell RNA-sequencing confirmed the concomitant activation of T and B cell responses in a germinal center-like manner within the nasal-associated lymphoid tissues (NALT), confirming its role as an inductive site that can lead to long-lasting immunity. The ability to elicit immunity in the respiratory tract has can prevent the initial establishment of infection in individuals and prevent disease transmission across humans.
Cell-ID: gene signature extraction and cell identity recognition at individual cell level
Authors: Akira Cortal , Loredana Martignetti , Emmanuelle Six , Antonio Rausell
Published: July 2020

The exhaustive exploration of human cell heterogeneity requires the unbiased identification of molecular signatures that can serve as unique cell identity cards for every cell in the body. However, the stochasticity associated with high-throughput single-cell sequencing has made it necessary to use clustering-based computational approaches in which the characterization of cell-type heterogeneity is performed at cell-subpopulation level rather than at full single-cell resolution. We present here Cell-ID, a clustering-free multivariate statistical method for the robust extraction of per-cell gene signatures from single-cell sequencing data. Cell-ID signatures allow unbiased cell identity recognition across different donors, tissues-of-origin, model organisms and single-cell omics technologies. Cell-ID is distributed as an open-source R software package:https://github.com/RausellLab/CelliD.
Bacterial dormancy: a subpopulation of viable but non-culturable cells demonstrates better fitness for revival
Authors: Wagley Sariqa , Morcrette Helen , Kovacs-Simon Andrea , Yang Zheng R. , Power Ann , Tennant Richard K. , Love John , Murray Neil , Titball Richard W. , Butler Clive S.
Published: July 2020

The viable but non culturable (VBNC) state is a condition in which bacterial cells are viable and metabolically active, but resistant to cultivation using a routine growth medium. We investigated the ability ofV. parahaemolyticusto form VBNC cells, and to subsequently become resuscitated. The ability to control VBNC cell formation in the laboratory allowed us to selectively isolate VBNC cells using fluorescence activated cell sorting, and to differentiate subpopulations based on their metabolic activity, cell shape and the ability to cause disease inGalleria mellonella. Our results showed that two key subpopulations (P1 and P2) ofV. parahaemolyticusVBNC cells exist and can remain dormant in the VBNC state for long periods. The two subpopulations displayed different abilities for revival under favourable conditions. Proteomic analysis of these subpopulations (at two different time points: 12 days (T12) and 50 days (T50) post VBNC) has also revealed that the proteome of P2 was more similar to that of the starting microcosm culture (T0) than the proteome of P1. The proteins that were significantly up and down regulated between the different VBNC populations were determined and significantly regulated proteins were assigned into 23 functional groups, the majority being included in metabolism functional categories. A lactate dehydrogenase (lldD) protein was significantly upregulated in all subpopulations of VBNC cells and is responsible for converting lactate to pyruvate. Deletion of the lactate dehydrogenase (RIMD2210633:ΔlldD) gene causes the cells to enter the VBNC state significantly faster than the wild-type, and exogenously adding lactate to VBNC cells aided resuscitation and extended the resuscitation window. Addition of pyruvate to the RIMD2210633:ΔlldDstrain restored the wild-type VBNC formation profile. This study suggests that lactate dehydrogenase plays a putative key role in regulating the VBNC state.
The first AI-based mobile application for antibiotic resistance testing
Authors: Pascucci Marco , Royer Guilhem , Adamek Jakub , Aristizabal David , Blanche Laetitia , Bezzarga Amine , Boniface-Chang Guillaume , Brunner Alex , Curel Christian , Dulac-Arnold Gabriel , Malou Nada , Nordon Clara , Runge Vincent , Samson Franck , Sebastian Ellen , Soukieh Dena , Vert Jean-Philippe , Ambroise Christophe , Madoui Mohammed-Amin
Published: July 2020

Antimicrobial resistance is a major global health threat and its development is promoted by antibiotic misuse. While disk diffusion antibiotic susceptibility testing (AST, also called antibiogram) is broadly used to test for antibiotic resistance in bacterial infections, it faces strong criticism because of inter-operator variability and the complexity of interpretative reading. Automatic reading systems address these issues, but are not always adapted or available to resource-limited settings. We present the first artificial intelligence (AI)-based, offline smartphone application for antibiogram analysis. The application captures images with the phone’s camera, and the user is guided throughout the analysis on the same device by a user-friendly graphical interface. An embedded expert system validates the coherence of the antibiogram data and provides interpreted results. The fully automatic measurement procedure of our application’s reading system achieves an overall agreement of 90% on susceptibility categorization against a hospital-standard automatic system and 98% against manual measurement (gold standard), with reduced inter-operator variability. The application’s performance showed that the automatic reading of antibiotic resistance testing is entirely feasible on a smartphone. Moreover our application is suited for resource-limited settings, and therefore has the potential to significantly increase patients’ access to AST worldwide.
Bimolecule detection for Extracellular Vesicle Screening
Authors: Kaneda Hisako , Ida Yui , Kuwahara Ryusuke , Sato Izumi , Nakano Takanari , Tokuda Haruhiko , Sato Tsuyoshi , Murakoshi Takayuki , Honke Koichi , Kotani Norihiro
Published: July 2020

Extracellular vesicle (EV) has been investigated for use in clinical testing in recent years. Specific EV surface proteins provide distinguishing characteristics, but are insufficient for more detailed classification of EVs. Here, we suggest a novel “Bimolecular surface antigen expressed in EV” (BiEV) as a potential indicator for more efficient EV screening. A BiEV can be identified using a previously developed method, enzyme-mediated activation of radical sources, to label the components proximal (within 20 nm) to a given molecule. We examined the screening of cancer cell-secreted EV (cEV) included in serum EVs from a model mouse for lung cancer. The cEV-specific BiEVs were first identified by through a comparison of serum EVs from wild-type and lung cancer mice, showing that the CHL1-SLC4A1 bimolecule was a significant candidate for cEV-specific BiEV. Enzyme-linked immunosorbent assay quantification of CHL1-SLC4A1 BiEV appeared to suggest a potential for cancer screening of these mice. Using the same protocols, we found that CHL1-caspase 14 BiEV was significantly elevated in lung cancer patients compared with healthy persons. A BiEV strategy may be able to make a contribution to more effective EV screening, resulting in novel biological and clinical applications.
Robust Rhythmogenesis via Spike Timing Dependent Plasticity
Authors: Socolovsky Gabi , Shamir Maoz
Published: July 2020

Rhythmic activity has been observed in numerous animal species ranging from insects to humans, and in relation to a wide range of cognitive tasks. Various experimental and theoretical studies have investigated rhythmic activity. The theoretical efforts have mainly been focused on the neuronal dynamics, under the assumption that network connectivity satisfies certain fine-tuning conditions required to generate oscillations. However, it remains unclear how this fine tuning is achieved.

Here we investigated the hypothesis that spike timing dependent plasticity (STDP) can provide the underlying mechanism for tuning synaptic connectivity to generate rhythmic activity. We addressed this question in a modeling study. We examined STDP dynamics in the framework of a network of excitatory and inhibitory neuronal populations that has been suggested to underlie the generation of oscillations in the gamma range. Mean field Fokker Planck equations for the synaptic weights dynamics are derived in the limit of slow learning. We drew on this approximation to determine which types of STDP rules drive the system to exhibit rhythmic activity, and demonstrate how the parameters that characterize the plasticity rule govern the rhythmic activity. Finally, we propose a novel mechanism that can ensure the robustness of self-developing processes, in general and for rhythmogenesis in particular.
SEPIA - SuscEptibility mapping PIpeline tool for phAse images
Authors: Chan Kwok-Shing , Marques José P.
Published: July 2020

Quantitative susceptibility mapping (QSM) is a physics-driven computational technique that has a high sensitivity in quantifying iron deposition based on MRI phase images. Furthermore, it has a unique ability to distinguish paramagnetic and diamagnetic contributions such as haemorrhage and calcification based on image contrast. These properties have contributed to a growing interest to use QSM not only in research but also in clinical applications. However, it is challenging to obtain high quality susceptibility map because of its ill-posed nature, especially for researchers who have less experience with QSM and the optimisation of its pipeline. In this paper, we present an open-source processing pipeline tool called SuscEptibility mapping PIpeline tool for phAse images (SEPIA) dedicated to the post-processing of MRI phase images and QSM. SEPIA connects various QSM toolboxes freely available in the field to offer greater flexibility in QSM processing. It also provides an interactive graphical user interface to construct and execute a QSM processing pipeline, simplifying the workflow in QSM research. The extendable design of SEPIA also allows developers to deploy their methods in the framework, providing a platform for developers and researchers to share and utilise the state-of-the-art methods in QSM.
Multiple-labeled antibodies behave like single emitters in photoswitching buffer
Authors: Helmerich Dominic A. , Beliu Gerti , Sauer Markus
Published: July 2020

The degree of labeling (DOL) of antibodies has so far been optimized for high brightness and specific and efficient binding. The influence of the DOL on the blinking performance of antibodies used indirectstochastic optical reconstruction microscopy (dSTORM) has so far attained limited attention. Here, we investigated the spectroscopic characteristics of IgG antibodies labeled at DOLs of 1.1- 8.3 with Alexa Fluor 647 (Al647) at the ensemble and single-molecule level. Multiple-Al647-labeled antibodies showed weak and strong quenching interactions in aqueous buffer but could all be used fordSTORM imaging with spatial resolutions of ∼ 20 nm independent of the DOL. Photon antibunching experiments in aqueous buffer demonstrate that the emission of multiple-Al647-labeled antibodies switches from classical to non-classical light in photoswitching buffer. We developed a model that explains the observed blinking of multiple-labeled antibodies and can be used advantageously to develop improved fluorescent probes fordSTORM experiments.
Ancient DNA ofRickettsia felisandToxoplasma gondiiimplicated in the death of a hunter-gatherer boy from South Africa, 2,000 years ago
Authors: Rifkin Riaan F. , Vikram Surendra , Ramond Jean-Baptiste J. , Cowan Don A. , Jakobsson Mattias , Schlebusch Carina M. , Lombard Marlize
Published: July 2020

The Stone Age record of South Africa provides some of the earliest evidence for the biological and cultural origins ofHomo sapiens. While there is extensive genomic evidence for the selection of polymorphisms in response to pathogen-pressure in sub-Saharan Africa, there is insufficient evidence for ancient human-pathogen interactions in the region. Here, we analysed shotgun metagenome libraries derived from the sequencing of a Later Stone Age hunter-gatherer child who lived near Ballito Bay, South Africa,c. 2,000 years ago. This resulted in the identification of DNA sequence reads homologous toRickettsia felis, and the reconstruction of an ancientR. felisgenome, the causative agent of typhus-like flea-borne rickettsioses. The concurrent detection of DNA reads derived fromToxoplasma gondii, the causative agent of toxoplasmosis, confirms the pre-Neolithic incidence of these pathogens in southern Africa. We demonstrate that anR. felisandT. gondiico-infection, exacerbated by various additional bacterial and parasitic pathogens, contributed to the ill-health and subsequent demise of the boy from Ballito Bay.
Twists and turns of the salicylate catabolism inAspergillus terreus
Authors: Martins Tiago M. , Martins Celso , Pereira Cristina Silva
Published: July 2020

In fungi, salicylate catabolism was believed to proceed only through the catechol branch of the 3-oxoadipate pathway, as showne.g.inAspergillus nidulans. However, the observation of a transient accumulation of gentisate upon cultivation ofAspergillus terreusin salicylate media questions this concept. To address this we have run a comparative analysis of the transcriptome of these two species after growth in salicylate using acetate as a control condition. The results revealed the high complexity of the salicylate metabolism inA. terreuswith the concomitant positive regulation of several pathways for the catabolism of aromatic compounds. This included the unexpected joint action of two pathways: the nicotinate and the 3-hydroxyanthranilate, possibly crucial for the catabolism of aromatics in this fungus. New genes participating in the nicotinate metabolism are here proposed, whereas the 3-hydroxyanthranilate catabolic pathway in fungi is described for the first time. The transcriptome analysis showed also for the two species an intimate relationship between salicylate catabolism and secondary metabolism. This study emphasizes that the central pathways for the catabolism of aromatic hydrocarbons in fungi hold many mysteries yet to be discovered.

IMPORTANCE

Aspergilli are versatile cell factories used in industry for production of organic acids, enzymes and pharmaceutical drugs. To date, organic acids bio-based production relies on food substrates. These processes are currently being challenged to switch to renewable non-food raw materials; a reality that should inspire the use of lignin derived aromatic monomers. In this context, Aspergilli emerge at the forefront of future bio-based approaches due to their industrial relevance and recognized prolific catabolism of aromatic compounds. Notwithstanding considerable advances in the field, there are still important knowledge gaps in the central catabolism of aromatic hydrocarbons in fungi. Here, we disclosed a novel central pathway, defying previous established ideas on the central metabolism of the aromatic amino acid tryptophan in Ascomycota. We also observed that the catabolism of the aromatic salicylate greatly activated the secondary metabolism, furthering the significance of using lignin derived aromatic hydrocarbons as a distinctive biomass source.
Tendon-derived biomimetic surface topographies induce phenotypic maintenance of tenocytesin vitro
Authors: Dede Eren Aysegul , Vasilevich Aliaksei , Eren E. Deniz , Sudarsanam Phanikrishna , Tuvshindorj Urandelger , de Boer Jan , Foolen Jasper
Published: July 2020

The tenocyte niche contains biochemical and biophysical signals that are needed for tendon homeostasis. The tenocyte phenotype is correlated with cell shapein vivoandin vitro, and shape-modifying cues are needed for tenocyte phenotypical maintenance. Indeed, cell shape changes from elongated to spread when cultured on a flat surface, and rat tenocytes lose the expression of phenotypical markers throughout five passages. We hypothesized that tendon gene expression can be preserved by culturing cells in the native tendon shape. To this end, we reproduced the tendon topographical landscape into tissue culture polystyrene, using imprinting technology. We confirmed that the imprints forced the cells into a more elongated shape, which correlated with the level of Scleraxis expression. When we cultured the tenocytes for seven days on flat surfaces and tendon imprints, we observed a decline in tenogenic marker expression on flat but not on imprints. This research demonstrates that native tendon topography is an important factor contributing to the tenocyte phenotype. Tendon imprints therefore provide a powerful platform to explore the effect of instructive cues originating from native tendon topography on guiding cell shape, phenotype and function of tendon-related cells.
Isoprenylcysteine carboxylmethyltransferase-based therapy for Hutchinson–Gilford progeria syndrome
Authors: Marcos-Ramiro Beatriz , Gil-Ordóñez Ana , Marín-Ramos Nagore I. , Ortega-Nogales Francisco J. , Balabasquer Moisés , Gonzalo Pilar , Rolas Loïc , Barkaway Anna , Nourshargh Sussan , Andrés Vicente , Martín-Fontecha Mar , López-Rodríguez María L. , Ortega-Gutiérrez Silvia
Published: July 2020

Progerin is a mutant prelamin A variant that causes Hutchinson–Gilford progeria syndrome (HGPS, progeria), a rare genetic disease characterized by premature aging and death in childhood. Although several therapeutic approaches have been explored in experimental models, clinical trials have shown very limited benefits in HGPS patients. Here, we describe the development of UCM-13207, a new potent inhibitor of isoprenylcysteine carboxylmethyltransferase (ICMT) that reduces progerin nuclear accumulation and ameliorates the typical alterations in progeroid human and mouse cells. UCM-13207 also improves phenotypic anomalies and extends lifespan in progerin-expressingLmnaG609G/G609Gmice. These results support the potential use of UCM-13207 as a new treatment for progeria.
The prevalence ofAngiostrongylus cantonensisin rodent hosts in China and several Asian countries: a systematic review and meta-analysis
Authors: Bai Huifang , Cao Yizhen , Chen Yunqiu , Zhang Lingmin , Wu Chunyun , Cheng Mei
Published: July 2020

Background

Angiostrogylus cantonensis(A.cantonensis) is a zoonotic parasitic nematode, with a worldwide distribution, causing eosinophilic meningitis or meningoencephalitis in humans. Although the biology ofA.cantonensisis relatively well known, little is understood about the transmission level in different zoogeographical regions, especially in Asia. Here, to evaluate the prevalence ofA.cantonensisin rodent hosts in China and several Asian countries, we conducted a systematic review registered with PROSPERO (CRD42020161665).

Methods

Records were selected systematically from 7 databases (Medline via to Pubmed, Web of science, Scopus, Google Scholar, CNKI, Wangfang, CBM). Forest plots and random-effects model were used to display pooled estimates. The Freeman-Tukey double arcsine transformation of R software was used to conduct meta-analysis and statistical significance was set at 0.05.

Results

A total of 67 studies met the inclusion criteria and were included in the systematic review and meta-analysis. The pooled prevalence estimates ofA.cantonensisinfection in rodents was 0.1003 (95%CI: 0.0765, 0.1268). There was significant heterogeneity in reported outcomes (p<0.0001). So we considered that there was no publication bias in the included studies.

Conclusion

TheA.cantonensisinfection rate among rodent hosts was still high in Asia, particularly in China, especially inRattus norvegicus, and thus comprehensive measures should be taken for rodent hosts control to avoid an angiostrongyliasis outbreak. Due to the wide distribution and movement of rodent hosts, people in all regions of China, even in other Asia area live at risk of an infection. Hence, the development of more reliable diagnostic tests will be key for an effective identification of cases as well as improved patient care. Consequently, further studies are required to updated strategies for controllingA.cantonensisinfection among human population.