bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Triage Tool of Artificial Intelligence-Assisted Diagnosis Aid System for Suspected COVID-19 Pneumonia in Fever Clinics
Authors: Feng Cong , Wang Lili , Chen Xin , Zhai Yongzhi , Zhu Feng , Chen Hua , Wang Yingchan , Su Xiangzheng , Huang Sai , Tian Lin , Zhu Weixiu , Sun Wenzheng , Zhang Liping , Han Qingru , Zhang Juan , Pan Fei , Chen Li , Zhu Zhihong , Xiao Hongju , Liu Yu , Liu Gang , Chen Wei , Li Tanshi
Published: March 2020

Background

Currently, the prevention and control of the novel coronavirus disease (COVID-19) outside Hubei province in China, and other countries have become more and more critically serious. We developed and validated a diagnosis aid model without computed tomography (CT) images for early identification of suspected COVID-19 pneumonia (S-COVID-19-P) on admission in adult fever patients and made the validated model available via an online triage calculator.

Methods

Patients admitted from Jan 14 to February 26, 2020 with the epidemiological history of exposure to COVID-19 were included [Model development (n = 132) and validation (n = 32)]. Candidate features included clinical symptoms, routine laboratory tests, and other clinical information on admission. Features selection and model development were based on the least absolute shrinkage and selection operator (LASSO) regression. The primary outcome was the development and validation of a diagnostic aid model for S-COVID-19-P early identification on admission.

Results

The development cohort contained 26 S-COVID-19-P and 7 confirmed COVID-19 pneumonia cases. The final selected features included 1 variable of demographic information, 4 variables of vital signs, 5 variables of blood routine values, 7 variables of clinical signs and symptoms, and 1 infection-related biomarker. The model performance in the testing set and the validation cohort resulted in the area under the receiver operating characteristic (ROC) curves (AUCs) of 0.841 and 0.938, the F-1 score of 0.571 and 0.667, the recall of 1.000 and 1.000, the specificity of 0.727 and 0.778, and the precision of 0.400 and 0.500. The top 5 most important features were Age, IL-6, SYS_BP, MONO%, and Fever classification. Based on this model, an optimized strategy for S-COVID-19-P early identification in fever clinics has also been designed.

Conclusions

S-COVID-19-P could be identified early by a machine-learning model only used collected clinical information without CT images on admission in fever clinics with a 100% recall score. The well-performed and validated model has been deployed as an online triage tool, which is available athttps://intensivecare.shinyapps.io/COVID19/.
Thioproline formation as a driver of formaldehyde toxicity inEscherichia coli
Authors: Patterson Jenelle A. , He Hai , Folz Jacob S. , Li Qiang , Wilson Mark A. , Fiehn Oliver , Bruner Steven D. , Bar-Even Arren , Hanson Andrew D.
Published: March 2020

Formaldehyde (HCHO) is a reactive carbonyl compound that formylates and cross-links proteins, DNA, and small molecules. It is of specific concern as a toxic intermediate in the design of engineered pathways involving methanol oxidation or formate reduction. The high interest in engineering these pathways is not, however, matched by engineering-relevant information on precisely why HCHO is toxic or on what damage-control mechanisms cells deploy to manage HCHO toxicity. The only well-defined mechanism for managing HCHO toxicity is formaldehyde dehydrogenase-mediated oxidation to formate, which is counterproductive if HCHO is a desired pathway intermediate. We therefore sought alternative HCHO damage-control mechanisms via comparative genomic analysis. This analysis associated homologs of theEscherichia coli pepPgene with HCHO-related one-carbon metabolism. Furthermore, deletingpepPincreased the sensitivity ofE. colito supplied HCHO but not other carbonyl compounds. PepP is a proline aminopeptidase that cleaves peptides of the general formula X-Pro-Y, yielding X + Pro-Y. HCHO is known to react spontaneously with cysteine to form the close proline analog thioproline (thiazolidine-4-carboxylate), which is incorporated into proteins and hence into proteolytic peptides. We therefore hypothesized that thioproline-containing peptides are toxic and that PepP cleaves these aberrant peptides. Supporting this hypothesis, PepP cleaved the model peptide Ala-thioproline-Ala as efficiently as Ala-Pro-Alain vitroandin vivo, and deletingpepPincreased sensitivity to supplied thioproline. Our data thus (i) provide biochemical genetic evidence that thioproline formation contributes substantially to HCHO toxicity and (ii) make PepP a candidate damage-control enzyme for engineered pathways having HCHO as an intermediate.
Neuron Type-Specific Translatomes in Spinal Cords of Naïve and Neuropathic Mice
Authors: Das Gupta R.R. , Scheurer L. , Pelczar P. , Ralvenius W.T. , Wildner H. , Zeilhofer H.U.
Published: March 2020

The spinal dorsal horn harbors a sophisticated and heterogeneous network of excitatory and inhibitory neurons that process peripheral signals encoding different sensory modalities. Although it has long been recognized that this network is crucial both for the separation and the integration of sensory signals of different modalities, the molecular identity of the underlying neurons and signaling mechanisms are still only partially understood. Here, we have used the translating ribosome affinity purification (TRAP) technique to map the translatomes of excitatory glutamatergic (VGLUT2+) and inhibitory GABA and/or glycinergic (VGAT+or Gad67+) neurons of the mouse spinal cord. Our analyses demonstrate that inhibitory and excitatory neurons are primarily set apart by the expression of genes encoding transcription factors or genes related to the production, release or re-uptake of their principal neurotransmitters (glutamate, GABA or glycine). Subsequent gene ontology (GO) term analyses revealed that neuropeptide signaling-related GO terms were highly enriched in the excitatory population. Eleven neuropeptide genes displayed largely non-overlapping expression patterns closely adhering to the laminar and hence also functional organization of the spinal cord grey matter, suggesting that they may serve as major determinants of modality-specific processing. Since this modality-specific processing of sensory input is severely compromised in chronic, especially neuropathic, pain, we also investigated whether peripheral nerve damage changes the neuron typespecific translatome. In summary, our results suggest that neuropeptides contribute to modalityspecific sensory processing in the spinal cord but also indicate that altered sensory encoding in neuropathic pain states occurs independent of major translatome changes in the spinal neurons.
CitrusKB: A Comprehensive Knowledge Base for Transcriptome and Interactome ofCitrusspp. Infected byXanthomonas citrisubsp.citriat Different Infection Stages
Authors: Ferrasa Adriano , Murata Mayara M. , Cofre Teresa D. C. G. , Cavallini Juliana S. , Peron Gustavo , Julião Maria H. M. , Belasque José , Ferreira Henrique , Ferro Maria Inês T. , Leite Rui P. , Penha Helen A. , Carvalho Flávia M. S. , Varani Alessandro M. , Herai Roberto H. , Ferro Jesus A.
Published: March 2020

Citrus canker type A is a serious disease caused byXanthomonas citrisubsp.citri(X. citri), which is responsible for severe losses to growers and to the citrus industry worldwide. To date, no canker-resistant citrus genotypes are available, and there is limited information regarding the molecular and genetic mechanisms involved in the early stages of the citrus canker development. Here, we present the knowledge base for transcriptome ofin vivocitrus interactome, the CitrusKB. This is the firstin vivointeractome database for different citrus cultivars, and it was produced to provide a valuable source of information on citrus and their interaction with the citrus canker bacteriumX. citri. The database provides tools for a user-friendly web interface to search and analyze a large amount of information regarding eight citrus cultivars with distinct levels of susceptibility to the disease and their interaction, at different stages of infection, with the citrus canker bacteriumX. citri. Currently, CitrusKB comprises a reference citrus genome and its transcriptome, expressed transcripts, pseudogenes and predicted genomic variations (SNPs and SSRs). The updating process will continue by incorporating annotations and analysis tools. We expect that CitrusKB may substantially contribute to the area of citrus genomics. CitrusKB is accessible athttp://bioinfo.deinfo.uepg.br/citrus. Users can download all the generated raw sequences and generated datasets by this study from the CitrusKB website.
Exercise promotes satellite cell contribution to myofibers in a load-dependent manner
Authors: Masschelein Evi , D’Hulst Gommaar , Zvick Joel , Hinte Laura , Soro-Arnaiz Inés , Gorski Tatiane , von Meyenn Ferdinand , Bar-Nur Ori , De Bock Katrien
Published: March 2020

Satellite cells (SCs) are required for muscle repair following injury and are involved in muscle remodeling upon muscular contractions. Exercise stimulates SC accumulation and myonuclear accretion. To what extent exercise training at different mechanical loads drive SC contribution to myonuclei however is unknown. By performing SC fate tracing experiments, we show that 8-weeks of voluntary wheel running increased SC contribution to myonuclei in mouse plantar flexor muscles in a load-dependent but fiber type-independent manner. Increased SC fusion however was not exclusively linked to muscle hypertrophy as wheel running without external load substantially increased SC fusion in the absence of fiber hypertrophy. Due to nuclear propagation, nuclear fluorescent fate tracing mouse models were inadequate to quantify SC contribution to myonuclei. Ultimately, by performing fate tracing at the DNA level, we show that SC contribution mirrors myonuclear accretion during exercise. Collectively, these findings provide direct evidence that mechanical load during exercise independently promotes SC contribution to existing myofibers.
CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci
Authors: Martinez-Fabregas J. , Wang L. , Pohler E. , Cozzani A. , Kazemian M. , Mitra S. , Moraga I.
Published: March 2020

Cytokines are highly pleiotropic ligands that critically contribute to a balanced immune response. We have an incomplete understanding of how cytokines elicit their functional pleiotropy, which has limited their therapeutic use. Here, using Interleukin-6 (IL-6) as a model system, we have performed detailed phosphoproteomic and transcriptomic studies in human Th-1 cells to address the molecular bases defining cytokine functional pleiotropy. We have identified CDK8 as a new negative regulator of STAT3 transcriptional activities that contributes to the diversification of IL-6 responses. We found that CDK8 is a major regulator of the IL-6 phosphoproteome and interacts with STAT3 in the nucleus upon IL-6 stimulation. Inhibition of CDK8 activity, using specific small molecules inhibitors, reduced the IL-6-induced phosphoproteome by 23% in Th-1 cells, including STAT3 Ser727 phosphorylation. This, in turn, resulted in retention of tyrosine phosphorylated STAT3 in the nucleus, which increased the binding of STAT3 to target DNA sites in the genome with a concomitant increase in STAT3 mediated transcriptional activity. Importantly, inhibition of CDK8 activity under Th-17 polarizing conditions resulted in an enhancement of Th-17 differentiation. Our results support a model where CDK8 regulates STAT3 transcriptional processivity via modulation of its gene loci resident time, critically contributing to tuning STAT3 mediated responses.
Kentrophoros magnussp. nov. (Ciliophora, Karyorelictea), a new flagship species of marine interstitial ciliates
Authors: Seah Brandon K. B. , Volland Jean-Marie , Leisch Nikolaus , Schwaha Thomas , Dubilier Nicole , Gruber-Vodicka Harald R.
Published: March 2020

The karyorelictean ciliateKentrophoroslacks a defined oral apparatus but has a dense coat of symbiotic bacteria that it consumes by phagocytosis. Body size, shape, and nuclear characters are variable in this genus. We formally describe a new species,K. magnusfrom Elba (Italy), which has unusual folding of its symbiont-bearing surface into pouch-like compartments, a body form that we term “pseudotrophosomal”.K. magnuscells are large (2100 ± 700 × 170 ± 23 μm in vivo), but contain only one micronucleus and two macronuclei, although these are much bigger than otherKentrophoros(widths 20 ± 2.5 and 31 ± 4.0 μm respectively inK. magnus). We also present morphological observations on a close relative from Twin Cayes (Belize), which also has relatively large nuclei (micronuclei 13 ± 1.5 μm, mature macronuclei 20 ± 2.8 μm), but unlikeK. magnus, it has on average 22 nuclei per cell, with different developmental stages of the macronuclei present simultaneously, and lacks pouch-like folding. Nuclear number and arrangement are important characters for karyorelicts. We suggest the use of a “nuclear formula” to simplify descriptions. Our discovery of large and morphologically distinctive new species underlines the incompleteness of our knowledge about meiofaunal ciliates.
EFA6B regulates a stop signal for collective invasion in breast cancer
Authors: Racha Fayad , Monserrat Vázquez Rojas , Mariagrazia Partisani , Pascal Finetti , Shiraz Dib , Virginie Virolle , Olivier Cabaud , Marc Lopez , Daniel Birnbaum , François Bertucci , Michel Franco , Frédéric Luton
Published: March 2020

Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes, however additional mutations provide selective advantages to the tumor cells to resist treatment and develop metastases, therefore identification of secondary mutations is of paramount importance. EFA6B (Exchange Factor for ARF6, B) expression is reduced in breast cancer. To study the pro-tumoral impact of the loss of EFA6B we have invalidated its gene in normal human mammary cells. We found that EFA6B knock-out triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal a new EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up new avenues for the treatment of invasive breast cancer.
The histone variant H2A.W and linker histone H1 co-regulate heterochromatin accessibility and DNA methylation
Authors: Bourguet Pierre , Picard Colette L. , Yelagandula Ramesh , Pélissier Thierry , Lorković Zdravko J. , Feng Suhua , Pouch-Pélissier Marie-Noëlle , Schmücker Anna , Jacobsen Steven E. , Berger Frédéric , Mathieu Olivier
Published: March 2020

In flowering plants, heterochromatin is demarcated by the histone variant H2A.W, elevated levels of the linker histone H1, and specific epigenetic modifications, such as high levels of DNA methylation at both CG and non-CG sites. How H2A.W regulates heterochromatin organization and interacts with other heterochromatic features is unclear. To analyze thein vivofunction of H2A.W, we created ah2a.wnull mutant via CRISPR-Cas9,h2a.w-2.We find that H2A.W antagonizes deposition of H1 at heterochromatin and that non-CG methylation and accessibility are moderately decreased inh2a.w-2heterochromatin. Compared to H1 loss alone, combined loss of H1 and H2A.W greatly increases accessibility and facilitates non-CG DNA methylation in heterochromatin, suggesting co-regulation of heterochromatic features by H2A.W and H1. Our results suggest that H2A.W helps maintain optimal heterochromatin accessibility and DNA methylation by promoting chromatin compaction together with H1, while also inhibiting excessive H1 incorporation.
Mouth magnetoencephalography: A unique perspective on the human hippocampus
Authors: Tierney Tim M. , Levy Andrew , Barry Daniel N. , Meyer Sofie S. , Shigihara Yoshihito , Everatt Matt , Mellor Stephanie , Lopez Jose David , Bestmann Sven , Holmes Niall , Roberts Gillian , Hill Ryan M , Boto Elena , Leggett James , Shah Vishal , Brookes Matthew J. , Bowtell Richard , Maguire Eleanor A. , Barnes Gareth R.
Published: March 2020

Traditional magnetoencephalographic (MEG) brain imaging scanners consist of a rigid sensor array surrounding the head; this means that they are maximally sensitive to superficial brain structures. New technology based on optical pumping means that we can now consider more flexible and creative sensor placement. Here we explored the magnetic fields generated by a model of the human hippocampus not only across scalp but also at the roof of the mouth. We found that simulated hippocampal sources gave rise to dipolar field patterns with one scalp surface field extremum at the temporal lobe and a corresponding maximum or minimum at the roof of the mouth. We then constructed a fitted dental mould to accommodate an Optically Pumped Magnetometer (OPM). We collected data using a previously validated hippocampal-dependent task to test the empirical utility of a mouth-based sensor, with an accompanying array of left and right temporal lobe OPMs. We found that the mouth sensor showed the greatest task-related theta power change. We also found that, as predicted by the simulations, the mouth sensor was anti-correlated with those on over the temporal lobes. We found that this sensor had a mild effect on the reconstructed power in the hippocampus (~10% change) but that coherence images between the mouth sensor and reconstructed source images showed a global maximum in the right hippocampus. We conclude that augmenting a scalp-based MEG array with sensors in the mouth shows unique promise for both basic scientists and clinicians interested in interrogating the hippocampus.
Zebrafish Ski7 tunes RNA levels during the oocyte-to-embryo transition
Authors: Cabrera Quio Luis Enrique , Schleiffer Alexander , Mechtler Karl , Pauli Andrea
Published: March 2020

Post-transcriptional mechanisms are crucial for the regulation of gene expression. These mechanisms are particularly important during rapid developmental transitions such as the oocyte-to-embryo transition, which is characterized by dramatic changes to the developmental program in the absence of nuclear transcription. Under these conditions, changes to the RNA content are solely dependent on RNA degradation. Although several mechanisms that promote RNA decay during embryogenesis have been identified, it remains unclear which cellular machineries contribute to remodeling the maternal transcriptome during the oocyte-to-embryo transition. Here, we focused on the auxiliary 3’-to-5’ degradation factor Ski7 in zebrafish as its mRNA peaks during this time frame. Homozygousski7mutant fish were viable and developed into morphologically normal adults, yet they had decreased fertility. Consistent with the idea that Ski7 participates in remodeling the transcriptome during the oocyte-to-embryo transition, transcriptome profiling identified stage-specific mRNA targets of Ski7. Genes upregulated inski7mutants were generally lowly expressed in wild type, suggesting that Ski7 maintains low transcript levels for this subset of genes. GO enrichment analyses of genes mis-regulated inski7mutants implicated Ski7 in the regulation of redox processes. This was confirmed experimentally by an increased resistance ofski7mutant embryos to reductive stress. Overall, our results provide first insights into the physiological role of vertebrate Ski7 as an important post-transcriptional regulator during the oocyte-to-embryo transition.
Methylglyoxal induces nuclear accumulation of p53 and γH2AX in normal and cancer cells
Authors: Veß Astrid , Hollemann Thomas
Published: March 2020

The formation and accumulation of methylglyoxal (MGO) is associated with age-related diseases such as diabetes, cancer and neurodegenerative disorders. MGO is the major precursor of non-enzymatic glycation of macromolecules affecting their function and structure. We now show for the first time that MGO stress not only led to cellular aging responses like DNA double-strand breaks indicated by an accumulation of γH2AX in the nucleus. We also observed an immediate increase of Ser15 phosphorylated p53 in the nucleus of MGO treated cell lines which will change the cellular expression pattern with adverse effects on the cell cycle and other cellular functions not necessarily related to aging.
Cortical inactivation does not block response enhancement in the superior colliculus
Authors: Kordecka Katarzyna , Foik Andrzej T. , Wierzbicka Agnieszka , Waleszczyk Wioletta J.
Published: March 2020

Repetitive visual stimulation is successfully used in a study on the visual evoked potential (VEP) plasticity in the visual system in mammals. Practicing visual tasks or repeated exposure to sensory stimuli can induce neuronal network changes in the cortical circuits and improve the perception of these stimuli. However little is known about the effect of visual training at the subcortical level. In the present study, we extend the knowledge showing positive results of this training in the rat’s superior colliculus (SC). In electrophysiological experiments, we showed that a single training session lasting several hours induces a response enhancement both in the primary visual cortex (V1) and in the SC. Further, we tested if collicular responses will be enhanced without V1 input. For this reason, we inactivated the V1 by applying xylocaine solution onto the cortical surface during visual training. Our results revealed that SC’s response enhancement was present even without V1 inputs and showed no difference in amplitude comparing to VEPs enhancement while the V1 was active. These data suggest that the visual system plasticity and facilitation can develop independently but simultaneously in different parts of the visual system.
Bar-seq strategies for the LeishGEdit toolbox
Authors: Beneke Tom , Gluenz Eva
Published: March 2020

The number of fully sequenced genomes increases steadily but the function of many genes remains unstudied. To accelerate dissection of gene function inLeishmaniaspp. and other kinetoplastids we developed previously a streamlined pipeline for CRISPR-Cas9 gene editing, which we termed LeishGEdit [1]. To facilitate high-throughput mutant screens we have adapted this pipeline by barcoding mutants with unique 17-nucleotide barcodes, allowing loss-of-function screens in mixed populations [2]. Here we present primer design and analysis tools that facilitate these bar-seq strategies. We have developed a standalone easy-to-use pipeline to design CRISPR primers suitable for the LeishGEdit toolbox for any given genome and have generated a list of 14,995 barcodes. Barcodes and oligos are now accessible through our websitewww.leishgedit.netallowing to pursue bar-seq experiments in all currently available TriTrypDB genomes (release 41). This will streamline CRISPR bar-seq assays in kinetoplastids, enabling pooled mutant screens across the community.

Highlights

Developing tools for pooled bar-seq mutant screens across the kinetoplastid community

Development of a standalone script to design primers suitable for the LeishGEdit toolbox

Generation of 14,995 barcodes that can be used for bar-seq strategies in kinetoplastids

Bar-seq primers for all TriTrypDB genomes (release 41) can be obtained fromwww.leishgedit.net
SPHERE: A novel approach to 3D and active sound localization
Authors: Gaveau V. , Coudert A. , Salemme R. , Koun E. , Desoche C. , Truy E. , Farne A. , Pavani F.
Published: March 2020

In everyday life, localizing a sound source in free-field entails more than the sole extraction of monaural and binaural auditory cues to define its location in the three-dimensions (azimuth, elevation and distance). In spatial hearing, we also take into account all the available visual information (e.g., cues to sound position, cues to the structure of the environment), and we resolve perceptual ambiguities through active listening behavior, exploring the auditory environment with head or/and body movements. Here we introduce a novel approach to sound localization in 3D named SPHERE (European patent n° WO2017203028A1), which exploits a commercially available Virtual Reality Head-mounted display system with real-time kinematic tracking to combine all of these elements (controlled positioning of a real sound source and recording of participants’ responses in 3D, controlled visual stimulations and active listening behavior). We prove that SPHERE allows accurate sampling of the 3D spatial hearing abilities of normal hearing adults, and it allowed detecting and quantifying the contribution of active listening. Specifically, comparing static vs. free head-motion during sound emission we found an improvement of sound localization accuracy and precisions. By combining visual virtual reality, real-time kinematic tracking and real-sound delivery we have achieved a novel approach to the study of spatial hearing, with the potentials to capture real-life behaviors in laboratory conditions. Furthermore, our new approach also paves the way for clinical and industrial applications that will leverage the full potentials of active listening and multisensory stimulation intrinsic to the SPHERE approach for the purpose rehabilitation and product assessment.
Transposable elements resistant to epigenetic resetting in the human germline are epigenetic hotspots for development and disease
Authors: Dietmann Sabine , Keogh Michael J , Tang Walfred , Magnusdottir Erna , Kobayashi Toshihiro , Chinnery Patrick F , Surani M. Azim
Published: March 2020

Despite the extensive erasure of DNA methylation in the early human germline, nearly eight percent of CpGs are resistant to the epigenetic resetting in the acutely hypomethylated primordial germ cells (week 7-9 hPGCs). Whether this occurs stochastically or represents relatively conserved layer of epigenetic information is unclear. Here we show that several predominantly hominoid-specific families of transposable elements (TEs) consistently resist DNA demethylation (henceforth called hPGC-methylated TEs or ‘escapees’) during the epigenetic resetting of hPGCs. Some of them undergo subsequent dynamic epigenetic changes during embryonic development. Our analysis of the fetal cerebral cortex also revealed multiple classes of young hPGC-methylated TEs within putative and established enhancers. Remarkably, specific hPGC-methylated TE subfamilies were associated with a multitude of adaptive human traits, including hair color and intelligence, and diseases including schizophrenia and Alzheimer’s disease. We postulate that hPGC-methylated TEs represent potentially heritable information within the germline with a role in human development and evolution.
DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain
Authors: Zhang Jing , Bellani Marina A. , James Ryan , Pokharel Durga , Zhang Yongqing , Reynolds John J. , McNee Gavin S. , Jackson Andrew P. , Stewart Grant S. , Seidman Michael M.
Published: March 2020

Duplication of mammalian genomes requires replisomes to overcome numerous impediments during passage through open (eu) and condensed (hetero) chromatin. Typically, studies of replication stress characterize mixed populations of challenged and unchallenged replication forks, averaged across S phase, and model a single species of “stressed” replisome. However, in cells containing potent obstacles to replication, we find two different lesion proximal replisomes. One is bound by the DONSON protein and is more frequent in early S phase, in regions marked by euchromatin. The other interacts with the FANCM DNA translocase, is more prominent in late S phase, and favors heterochromatin. The two forms can also be detected in unstressed cells. CHIP-seq of DNA associated with DONSON or FANCM confirms the bias of the former towards regions that replicate early and the skew of the latter towards regions that replicate late.
From iron to antibiotics: Identification of conserved bacterial-fungal interactions across diverse partners
Authors: Pierce Emily C. , Morin Manon , Little Jessica C. , Liu Roland B. , Tannous Joanna , Keller Nancy P. , Wolfe Benjamin E. , Pogliano Kit , Sanchez Laura M. , Dutton Rachel J.
Published: March 2020

Microbial interactions are major determinants in shaping microbiome structure and function. Although fungi are found across diverse microbiomes, the mechanisms through which fungi interact with other species remain largely uncharacterized. In this work, we explore the diversity of ways in which fungi can impact bacteria by characterizing interaction mechanisms across 16 different bacterial-fungal pairs, involving 8 different fungi and 2 bacteria (Escherichia coliandPseudomonas psychrophila). Using random barcode transposon-site sequencing (RB-TnSeq), we identified a large number of bacterial genes and pathways important in fungal interaction contexts. Within each interaction, fungal partners elicit both antagonistic and beneficial effects. Using a panel of phylogenetically diverse fungi allowed us to identify interactions that were conserved across all species. Our data show that all fungi modulate the availability of iron and biotin, suggesting that these may represent conserved bacterial-fungal interactions. Several fungi also appear to produce previously uncharacterized antibiotic compounds. Generating a mutant in a master regulator of fungal secondary metabolite production showed that fungal metabolites are key shapers of bacterial fitness profiles during interactions. This work demonstrates a diversity of mechanisms through which fungi are able to interact with bacterial species. In addition to many species-specific effects, there appear to be conserved interaction mechanisms which may be important across microbiomes.
Evolution of an enzyme conformational ensemble guides design of an efficient biocatalyst
Authors: Broom Aron , Rakotoharisoa Rojo V. , Thompson Michael C. , Zarifi Niayesh , Nguyen Erin , Mukhametzhanov Nurzhan , Liu Lin , Fraser James S. , Chica Roberto A.
Published: March 2020

The creation of artificial enzymes is a key objective of computational protein design. Althoughde novoenzymes have been successfully designed, these exhibit low catalytic efficiencies, requiring directed evolution to improve activity. Here, we used room-temperature X-ray crystallography to study changes in the conformational ensemble during evolution of the designed Kemp eliminase HG3 (kcat/KM160 M−1s−1). We observed that catalytic residues were increasingly rigidified, the active site became better pre-organized, and its entrance was widened. Based on these observations, we engineered HG4, an efficient biocatalyst (kcat/KM120,000 M−1s−1) containing active-site mutations found during evolution but not distal ones. HG4 structures revealed that its active site was pre-organized and rigidified for efficient catalysis. Our results show how directed evolution circumvents challenges inherent to enzyme design by shifting conformational ensembles to favor catalytically-productive sub-states, and suggest improvements to the design methodology that incorporate ensemble modeling of crystallographic data.
HIV-1 Vpr-induced Proinflammatory Response and Apoptosis are Mediated through the Sur1-Trpm4 Channel in Astrocytes
Authors: Li Ge , Makar Tapas , Gerzanich Volodymyr , Kalakonda Sudhakar , Ivanova Svetlana , Pereira Edna F. R. , Simard J. Marc , Zhao Richard Y.
Published: March 2020

There are about 38 million people currently living with HIV/AIDS worldwide. Successful treatment with combinational antiretroviral therapies (cART) can eliminate active replicating viruses and prolong lives to nearly normal lifespans. However, the new challenge faced by more than half of those HIV-infected and aging patients is chronic CNS neuroinflammation, which leads to HIV-associated neurocognitive disorders (HAND). While severe and progressive HAND has decreased significantly due to cART, chronic HAND often persists, resulting in high rates of delirium, dementia and depression that could lead to suicide. Indeed, the risk of suicide mortality in HIV-infected persons is significantly higher than in HIV-uninfected counterparts. Nevertheless, the mechanism of neuropathogenesis underlying HAND is not well understood. HAND is typically characterized by HIV-mediated glial neuroinflammation and neurotoxicity. Interestingly, the severity of some HAND does not always correlate with the levels of HIV, but rather with glial activation, suggesting other HIV-associated factors, not the whole virusper se, contribute to those HAND. HIV-1 viral protein R (Vpr) might be one of those viral factors, because Vpr induces neuroinflammation and causes neuronal apoptosis. Theobjectiveof this study was to delineate the specific role(s) of Vpr in activation of host neuroinflammation and neurotoxicity, as well as its contribution to HAND.

In this report, we show correlations between HIV expression and activation of proinflammatory markers (TLR4, TNFα, and NFκB) and the Sur1-Trpm4 channel in astrocytes of HIV-infected postmortem human and transgenic mouse brain tissues. We further show that Vpr alone activate the same set of proinflammatory markers in an astrocytic cell line SNB19. Vpr-induced host cell proinflammatory responses result in apoptotic cell death. Together, our data suggest that HIV-1 Vpr-induced proinflammatory response and apoptotic cell death are mediated through the Sur1-Trpm4 channel in astrocytes.
An inverted Caveolin-1 topology defines a novel exosome secreted from prostate cancer cells
Authors: Ariotti Nicholas , Wu Yeping , Okano Satomi , Gambin Yann , Follett Jordan , Rae James , Ferguson Charles , Teasdale Rohan D. , Alexandrov Kirill , Meunier Frederic A. , Hill Michelle M. , Parton Robert G.
Published: March 2020

Caveolin-1 (Cav1) expression and secretion is associated with prostate cancer (PCa) disease progression but the mechanisms underpinning Cav1 release remain poorly understood. Numerous studies have shown Cav1 can be secreted within exosome-like vesicles, but antibody-mediated neutralization can mitigate PCa progression; this is suggestive of an inverted (non-exosomal) Cav1 topology. Here we show that Cav1 can be secreted from specific PCa types in an inverted vesicle-associated form consistent with the features of bioactive Cav1 secretion. Characterization of the isolated vesicles by electron microscopy, single molecule fluorescent microscopy and proteomics reveals they represent a novel class of exosomes ∼40 nm in diameter containing ∼50-60 copies of Cav1 and strikingly, are released via a non-canonical secretory autophagy pathway. This study provides novel insights into a mechanism whereby Cav1 translocates from a normal plasma membrane distribution to an inverted secreted form implicated in PCa disease progression.
Automated design and optimization of multitarget schizophrenia drug candidates by deep learning
Authors: Tan Xiaoqin , Jiang Xiangrui , He Yang , Zhong Feisheng , Li Xutong , Xiong Zhaoping , Li Zhaojun , Liu Xiaohong , Cui Chen , Zhao Qingjie , Xie Yuanchao , Yang Feipu , Wu Chunhui , Shen Jingshan , Zheng Mingyue , Wang Zhen , Jiang Hualiang
Published: March 2020

Complex neuropsychiatric diseases such as schizophrenia require drugs that can target multiple G protein-coupled receptors (GPCRs) to modulate complex neuropsychiatric functions. Here, we report an automated system comprising a deep recurrent neural network (RNN) and a multitask deep neural network (MTDNN) to design and optimize multitargeted antipsychotic drugs. The system successfully generates novel molecule structures with desired multiple target activities, among which high-ranking compound3was synthesized, and demonstrated potent activities against dopamine D2, serotonin 5-HT1Aand 5-HT2Areceptors. Hit expansion based on the MTDNN was performed, 6 analogs of compound3were evaluated experimentally, among which compound8not only exhibited specific polypharmacology profiles but also showed antipsychotic effect in animal models with low potential for sedation and catalepsy, highlighting their suitability for further preclinical studies. The approach can be an efficient tool for designing lead compounds with multitarget profiles to achieve the desired efficacy in the treatment of complex neuropsychiatric diseases.

Graphical abstract
Gaze-evoked deformations of the optic nerve head in thyroid eye disease
Authors: Fisher Liam K. , Wang Xiaofei , Tun Tin A. , Chung Hsi-Wei , Milea Dan , Girard Michaël J.A.
Published: March 2020

Purpose

To assess gaze evoked deformations of the optic nerve head (ONH) in thyroid eye disease (TED), using computational modelling and optical coherence tomography (OCT).

Methods

Multiple finite element models were constructed: One model of a healthy eye, and two models mimicking effects of TED; one with proptosis and another with extraocular tissue stiffening. Two additional hypothetical models had extraocular tissue softening or no extraocular tissue at all. Horizontal eye movements were simulated in these models.

OCT images of the ONH of 10 healthy volunteers and 1 patient with TED were taken in primary gaze. Additional images were recorded in the same subjects performing eye movements in adduction and abduction.

The resulting ONH deformation in the models and human subjects was measured by recording the ‘tilt angle’ (relative antero-posterior deformation of the Bruch’s membrane opening). Effective stress was measured in the peripapillary sclera of the models.

Results

In our computational models the eyes with proptosis and stiffer extraocular tissue had greater gaze-evoked deformations than the healthy eye model, while the models with softer or no extraocular tissue had lesser deformations, in both adduction and abduction. Scleral stress correlated with the tilt angle measurements.

In healthy subjects, the mean tilt angle was 1.46° ± 0.25 in adduction and −0.42° ± 0.12 in abduction. The tilt angle measured in the subject with TED was 5.37° in adduction and −2.21° in abduction.

Conclusions

Computational modelling and experimental observation suggest that TED can cause increased gaze-evoked deformations of the ONH.
ZeroCostDL4Mic: an open platform to use Deep-Learning in Microscopy
Authors: Chamier Lucas von , Laine Romain F. , Jukkala Johanna , Spahn Christoph , Krentzel Daniel , Nehme Elias , Lerche Martina , Hernández-Pérez Sara , Mattila Pieta K. , Karinou Eleni , Holden Séamus , Solak Ahmet Can , Krull Alexander , Buchholz Tim-Oliver , Jones Martin L. , Royer Loïc A , Leterrier Christophe , Shechtman Yoav , Jug Florian , Heilemann Mike , Jacquemet Guillaume , Henriques Ricardo
Published: March 2020

The resources and expertise needed to use Deep Learning (DL) in bioimaging remain significant barriers for most laboratories. We presenthttps://github.com/HenriquesLab/ZeroCostDL4Mic/wiki, a platform simplifying access to DL by exploiting the free, cloud-based computational resources of Google Colab.https://github.com/HenriquesLab/ZeroCostDL4Mic/wikiallows researchers to train, evaluate, and apply key DL networks to perform tasks including segmentation, detection, denoising, restoration, resolution enhancement and image-to-image translation. We demonstrate the application of the platform to study multiple biological processes.
Aggregated spatio-temporal division patterns emerge from reoccurring divisions of neural stem cells
Authors: Lupperger V. , Marr C. , Chapouton P.
Published: March 2020

The regulation of quiescence and cell cycle entry is pivotal for the maintenance of stem cell populations. Regulatory mechanisms however are poorly understood. In particular it is unclear how the activity of single stem cells is coordinated within the population, or if cells divide in a purely random fashion. We addressed this issue by analyzing division events in an adult neural stem cell (NSC) population of the zebrafish telencephalon. Spatial statistics and mathematical modeling of over 80,000 NSCs in 36 brains revealed weakly aggregated, non-random division patterns in space and time. Analyzing divisions at two timepoints allowed us to infer cell cycle and S-phase lengths computationally. Interestingly, we observed rapid cell cycle re-entries in roughly 15% of newly born NSCs. In agent based simulations of NSC populations, this re-dividing activity sufficed to induce aggregated spatio-temporal division patterns that matched the ones observed experimentally. In contrast, omitting re-divisions lead to a random spatio-temporal distribution of dividing cells. Spatio-temporal aggregation of dividing stem cells can thus emerge from the cell’s history, regardless of possible feedback mechanisms in the population.
The active form of quinol-dependent nitric oxide reductase from Neisseria meningitidis is a dimer
Authors: Jamali M. Arif M. , Gopalasingam Chai C. , Johnson Rachel M. , Tosha Takehiko , Muramoto Kazumasa , Muench Stephen P. , Antonyuk Svetlana V. , Shiro Yoshitsugu , Hasnain Samar S.
Published: March 2020

Neisseria meningitidis is carried by nearly a billion humans, causing developmental impairment and over 100 000 deaths a year. A quinol-dependent nitric oxide reductase (qNOR) plays a critical role in the survival of the bacterium in the human host. X-ray crystallographic analyses of qNOR, including that from N. meningitidis (NmqNOR) reported here at 3.15 Å resolution, show monomeric assemblies, despite the more active dimeric sample being used for crystallization. Cryo-electron microscopic analysis of the same chromatographic fraction of NmqNOR, however, revealed a dimeric assembly at 3.06 Å resolution. It is shown that zinc (which is used in crystallization) binding near the dimer-stabilizing TMII region contributes to the disruption of the dimer. A similar destabilization is observed in the monomeric (∼85 kDa) cryo-EM structure of a mutant (Glu494Ala) qNOR from the opportunistic pathogen Alcaligenes (Achromobacter) xylosoxidans, which primarily migrates as a monomer. The monomer–dimer transition of qNORs seen in the cryo-EM and crystallographic structures has wider implications for structural studies of multimeric membrane proteins. X-ray crystallographic and cryo-EM structural analyses have been performed on the same chromatographic fraction of NmqNOR to high resolution. This represents one of the first examples in which the two approaches have been used to reveal a monomeric assembly in crystallo and a dimeric assembly in vitrified cryo-EM grids. A number of factors have been identified that may trigger the destabilization of helices that are necessary to preserve the integrity of the dimer. These include zinc binding near the entry of the putative proton-transfer channel and the preservation of the conformational integrity of the active site. The mutation near the active site results in disruption of the active site, causing an additional destabilization of helices (TMIX and TMX) that flank the proton-transfer channel helices, creating an inert monomeric enzyme.
My name is bond, Pecorino Bond
Authors: Paoloni Paola , Modaffari Giuseppe , Paoloni Niccolò
Published: March 2020

Purpose

The aim of this paper is to analyze how “mini-bonds,” an innovative financial tool for Italian small and medium-sized enterprises (SMEs), can contribute to the development and sustainability of the agri-food sector and its local products, such as Pecorino Cheese.

Design/methodology/approach

The study was conducted as a qualitative case study applying the CAOS (“characteristics, ambience, organization, start-up”) model. This model makes it possible to describe all variables that affect a company in a given economic context.

Findings

In Sardinia, a small island to the southwest of Italy, there are more than 60,000 agricultural enterprises, 60 percent of which are shepherding operations. Obtaining financial resources is a constant challenge, often related to the uncertainties inherent in seasonal activities. This paper explores how a mini-bond was implemented to promote the development and sustainability of Pecorino Cheese.

Research limitations/implications

Limitations are chiefly related to the short observation period—the bond was first issued in 2018—and to the narrow geographical base of observation.

Originality/value

This research contributes to the expanding body of literature on innovative financial tools for the promotion and development of the local agri-food heritage. It may be useful to practitioners currently researching and developing growth strategies for companies. Existing barriers to credit access are among the most important causes of the lack of development of SMEs, especially in Italy where SMEs represent the principal type of new businesses in the agri-food sector, and their economic success is so dependent on seasonality. In February 2019, the Pecorino case played a role in the Italian government stepping in to avoid the collapse of the price of milk. Future research will focus on the analysis of specific economic results of the financial operations described herein, and will further focus on possibly similar cases of local products making use of innovative financial tools.
Persuasiveness of organic agricultural products
Authors: Chou Feng-sha , Wang Chih-Chien , Lai Ming-Cheng , Tung Chien-Hui , Yang Yann-Jy , Tsai Kuen-Hung
Published: March 2020

Purpose

The study discusses organic agricultural product persuasion using an empirical survey. This study argued that strong argument persuasive advertising message would trigger individuals' self-reference to the harm of pesticide residue in non-organic agricultural product, which would raise their purchase intention of organic agricultural product.

Design/methodology/approach

The present study conducted an empirical investigation in Taiwan by recruiting 527 Taiwanese participants using the convenience sampling procedure. The current research performed structural equation modeling analysis and used LISREL software to report the analytical results.

Findings

Individuals with health consciousness may perceive a high-level risk of non-organic agricultural product, which would raise individuals' fear perception to the harm of pesticide residue. Fear perception will increase individual's purchase intention of organic agricultural product. Results can help industry practitioners benefit from the results by enabling them to develop their advertising strategy for organic food.

Originality/value

Results can help industry practitioners benefit from the results by enabling them to develop their advertising strategy for organic food.
Does (un)-related variety promote regional innovation in China? Industry versus services sector
Authors: Yang Nana , Liu Qiming , Qi Yu
Published: March 2020

Purpose

Although recent studies have increased attention on the effects of related and unrelated variety on innovation, a Chinese test has until now been missing from the literature. This paper aims to investigate how related and unrelated variety affect regional innovation in Chinese provinces. In particular, emphasis was placed on differentiating the analysis for the industry and services sectors at a detailed sectoral level.

Design/methodology/approach

This paper’s sample is composed of 30 provinces in China from 2003 to 2016. Feasible generalized least squares was used to estimate the effects of related and unrelated variety on regional innovation.

Findings

The results show that related variety in all sectors promotes regional innovation, whereas unrelated variety in all sectors does not play a role. In-depth analyses were performed by comparing the industry and services sectors. Only related variety in the industry sector and unrelated variety in the services sector promote regional innovation, whereas unrelated variety in the industry sector exerts a negative effect. After dividing the country into eastern, central and western regions, different findings appear in the sub-samples.

Originality/value

This study contributes to the literature on evolutionary economic geography and innovation by exploring how related and unrelated variety promote regional innovation in a developing country context (China). It also sheds light on the sectoral and regional differences in the influence of related and unrelated variety on regional innovation.