bluuebunny/crossref_metadata_2025 huggingface dataset:
Salinicoccus cyprini sp. nov., isolated from the gut of mirror carp, Cyprinus carpio var. specularis
Authors: Talwar Chandni , Singh Amit Kumar , Choksket Stanzin , Korpole Suresh , Lal Rup , Negi Ram Krishan
Published: June 2020

A novel orange to pink coloured bacterial strain designated as CT19T was isolated from the gastrointestinal tract of mirror carp, Cyprinus carpio var. specularis (Lacepède, 1803) collected from the Gobind Sagar reservoir at village Lathiani, Una, Himachal Pradesh, India. Cells of the strain were found to be aerobic, Gram-stain-positive, non-motile and non-spore-forming coccoids. Based on the 16S rRNA gene sequence, the strain was closely related to

Salinicoccus hispanicus

J-82T (=DSM 5352T; 97.4 %), followed by

S. sesuvii

CC-SPL15-2T (=DSM 23267T; 96.4 %),

S. amylolyticus

JC304T (=KCTC 33661T; 95.6 %) and

S. roseus

DSM 5351T (95.4 %). Identity with all other members of the genus were <94.5 %. The draft genome of strain CT19T was assembled to 2.4 Mbp with a G+C content of 47.9 mol%. Average nucleotide identity and digital DNA–DNA hybridization values between strain CT19T and

S. hispanicus

J-82T were found to be 85.9 and 31.3% respectively which is far below the threshold for species delineation. Iso-C15 : 0, anteiso-C15 : 0, iso-C17 : 0, C16 : 0 and anteiso-C17 : 0 were the major cellular fatty acids of strain CT19T. Major polar lipids were diphosphatidylglycerol, phosphatidylgylcerol and an unidentified glycolipid. Respiratory quinone system was composed of menaquinone-6 and major cell wall amino acid was l-lysine. Based on phylogenomic, physiological and biochemical characteristics, strain CT19T represents a novel species of the genus

Salinicoccus

for which the name Salinicoccus cyprini sp. nov. is proposed. The type strain is CT19T (=KCTC 43022T =CCM 8886T=MCC 3834T).
Cupriavidus agavae sp. nov., a species isolated from Agave L. rhizosphere in northeast Mexico
Authors: Arroyo-Herrera Ivan , Maldonado-Hernández Jessica , Rojas-Rojas Fernando-Uriel , Meza-Radilla Georgina , Larios-Serrato Violeta , Vásquez-Murrieta María-Soledad , Whitman William B. , Estrada-de los Santos Paulina
Published: June 2020

During the isolation of bacteria from the Agave L. rhizosphere in northeast Mexico, four strains with similar BOX-PCR patterns were collected. The 16S rRNA gene sequences of all four strains were very similar to each other and that of the type strains of

Cupriavidus metallidurans

CH34T (98.49 % sequence similarity) and

Cupriavidus necator

N-1T (98.35 %). The genome of strain ASC-9842T was sequenced and compared to those of other

Cupriavidus

species. ANIb and ANIm values with the most closely related species were lower than 95%, while the in silico DNA–DNA hybridization values were also much lower than 70 %, consistent with the proposal that they represent a novel species. This conclusion was supported by additional phenotypic and chemotaxonomic analyses. Therefore, the name Cupriavidus agavae sp. nov. is proposed with the type strain ASC-9842T (=LMG 26414T=CIP 110327T).
Molecular simulation of SARS-CoV-2 spike protein binding to pangolin ACE2 or human ACE2 natural variants reveals altered susceptibility to infection
Authors: Wang Jingfang , Xu Xintian , Zhou Xinbo , Chen Ping , Liang Huiying , Li Xuan , Zhong Wu , Hao Pei
Published: June 2020

We constructed complex models of SARS-CoV-2 spike protein binding to pangolin or human ACE2, the receptor for virus transmission, and estimated the binding free energy changes using molecular dynamics simulation. SARS-CoV-2 can bind to both pangolin and human ACE2, but has a significantly lower binding affinity for pangolin ACE2 due to the increased binding free energy (9.5 kcal mol−1). Human ACE2 is among the most polymorphous genes, for which we identified 317 missense single-nucleotide variations (SNVs) from the dbSNP database. Three SNVs, E329G (rs143936283), M82I (rs267606406) and K26R (rs4646116), had a significant reduction in binding free energy, which indicated higher binding affinity than wild-type ACE2 and greater susceptibility to SARS-CoV-2 infection for people with them. Three other SNVs, D355N (rs961360700), E37K (rs146676783) and I21T (rs1244687367), had a significant increase in binding free energy, which indicated lower binding affinity and reduced susceptibility to SARS-CoV-2 infection.
Reply to Li et al. “IsOculudentavisa bird or even archosaur?”
Authors: O’Connor Jingmai , Xing Lida , Chiappe Luis , Schmitz Lars , Li Gang , Yi Qiru
Published: June 2020

We welcome any new interpretation or alternative hypothesis regarding the taxonomic affinity of the enigmaticOculudentavis khaungraae. However, here we demonstrate that Li et al. have failed to provide conclusive evidence for the reidentification of HPG-15-3 as a squamate. We analyse this specimen in a matrix that includes a broad sample of diapsid reptiles and resolve support for this identification only when no avian taxa are included. Regardless of whether this peculiar skull belongs to a tiny bird or to a bizarre new group of lizards, the holotype ofOculudentavis khaungraaeis a very interesting and unusual specimen, the discovery of which represents an important contribution to palaeontology. Its discovery documents a potential new case of convergent evolution in reptiles, while highlighting the importance of amber deposits for documenting taxa not recorded in sedimentary deposits.
LayNii: A software suite for layer-fMRI
Authors: Huber Laurentius (Renzo) , Poser Benedikt A. , Bandettini Peter A. , Arora Kabir , Wagstyl Konrad , Cho Shinho , Goense Jozien , Nothnagel Nils , Morgan Andrew Tyler , van den Hurk Job , Müller Anna K , Reynolds Richard C. , Glen Daniel R. , Goebel Rainer , Gulban Omer Faruk
Published: June 2020

High-resolution fMRI in the sub-millimeter regime allows researchers to resolve brain activity across cortical layers and columns non-invasively. While these high-resolution data make it possible to address novel questions of directional information flow within and across brain circuits, the corresponding data analyses are challenged by MRI artifacts, including image blurring, image distortions, low SNR, and restricted coverage. These challenges often result in insufficient spatial accuracy of conventional analysis pipelines. Here we introduce a new software suite that is specifically designed for layer-specific functional MRI: LayNii. This toolbox is a collection of command-line executable programs written in C/C++ and is distributed open-source and as pre-compiled binaries for Linux, Windows, and macOS. LayNii is designed for layer-fMRI data that suffer from SNR and coverage constraints and thus cannot be straightforwardly analyzed in alternative software packages. Some of the most popular programs of LayNii contain ‘layerification’ and columnarization in the native voxel space of functional data as well as many other layer-fMRI specific analysis tasks: layer-specific smoothing, model-based vein mitigation of GE-BOLD data, quality assessment of artifact dominated sub-millimeter fMRI, as well as analyses of VASO data.

Highlights

A new software toolbox is introduced for layer-specific functional MRI: LayNii.

LayNii is a suite of command-line executable C++ programs for Linux, Windows, and macOS.

LayNii is designed for layer-fMRI data that suffer from SNR and coverage constraints.

LayNii performs layerification in the native voxel space of functional data.

LayNii performs layer-smoothing, GE-BOLD deveining, QA, and VASO analysis.

Abstract Figure

Graphical abstract
Identification of the Molecular Basis of Anti-fibrotic Effects of Soluble Guanylate Cyclase Activator Using the Human Lung Fibroblast Phosphoproteome
Authors: Kim Sunhwa , Saigal Ashmita , Zhao Weilong , Amini Peyvand , Tamburino Alex M. , Raghavan Subharekha , Hoek Maarten
Published: June 2020

Idiopathic pulmonary fibrosis (IPF) is an irreversible and progressive fibrotic lung disease. Advanced IPF patients often demonstrate pulmonary hypertension, which severely impairs patients’ quality of life. The critical physiological roles of soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway have been well characterized in vasodilation and the corresponding therapies and pathway agonists have shown clinical benefits in treating hypertension. In recent years, many preclinical studies have demonstrated anti-fibrotic efficacy of sGC-cGMP activation in various experimental fibrosis models but the molecular basis of the efficacy in these models are not well understood. Also, sGC pathway agonism has demonstrated encouraging clinical benefits in advanced IPF patients (NCT00517933). Here, we have revealed the novel phosphorylation events downstream of sGC activation in human lung fibroblasts using phosphoproteomics. sGCact A, a potent and selective sGC activator, significantly attenuated more than 2,000 phosphorylation sites. About 20% of phosphorylation events, attenuated by transforming growth factor β (TGFβ), a master regulator of fibrosis, were further dysregulated in the sGCact A co-treated lung fibroblasts. The overall magnitude and diversity of the sGCact A phosphoproteome was extensive. Further investigation would be required to understand how these newly identified changes facilitate human pulmonary fibrosis.
Predicting targets and costs for feral-cat reduction on large islands using stochastic population models
Authors: Venning Kathryn R. W. , Saltré Frédérik , Bradshaw Corey J. A.
Published: June 2020

Feral cats are some of the most destructive invasive predators worldwide, particularly in insular environments; hence, density-reduction campaigns are often applied to alleviate the predation mortality they add to native fauna. Density-reduction and eradication efforts are costly procedures with important outcomes for native fauna recovery, so they require adequate planning to be successful. These plans need to include empirical density-reduction models that can guide yearly culling quotas, and resource roll-out for the duration of the culling period. This ensures densities are reduced over the long term and that no resources are wasted. We constructed a stochastic population model with cost estimates to test the relative effectiveness and cost-efficiency of two main culling scenarios for a 10-year eradication campaign of cats on Kangaroo Island, Australia: (1) constant proportional annual cull (one-phase), and (2) high initial culling followed by a constant proportional maintenance cull (two-phase). A one-phase cull of at least 0.35 of the annual population size would reduce the final population to 0.1 of its original size, while a two-phase cull with an initial cull of minimum 0.6 and minimum 0.5 maintenance cull would reduce the final population to 0.01 of its initial size by 2030. Cost estimates varied widely depending on the methods applied (shooting, trapping, aerial poison baits,Felixer™ poison-delivery system), but using baiting, trapping andFelixerswith additional shooting to meet culling quotas was the most cost-effective combination (minimum cost: AU$19.56 million; range: AU$16.87 million–AU$20.69 million). Our model provides an adaptable and general assessment tool for cat reductions in Australia and potentially elsewhere, and provides relative culling costs for the Kangaroo Island programme specifically.
Brief Report: Test-Retest Reliability of Explicit Auditory Processing Measures
Authors: Saito Kazuya , Sun Hui , Tierney Adam
Published: June 2020

In this brief report, we examined the test-retest reliability of our in-house explicit auditory processing measures in the context of 30 L1 and L2 English users. The participants took the same test battery which consisted of a total of four discrimination tasks (encoding acoustic details of formant, pitch, duration, and rise time) and two reproduction tasks (repeating novel melodic and rhythmic patterns) at Days 1 and 2. According to the results, the participants’ initial and second test scores demonstrated medium-to-large associations (r= .562-.907). The results suggest that the tests can tap into various dimensions of individuals’ auditory acuity and integration abilities.
How to better communicate exponential growth of infectious diseases
Authors: Schonger Martin , Sele Daniela
Published: June 2020

Exponential growth bias is the phenomenon that humans underestimate exponential growth. In the context of infectious diseases, this bias may lead to failure to understand the effectiveness of non-pharmaceutical interventions (NPIs). Communicating the same scenario in different ways (framing) has been found to have a large impact on people’s evaluations and behavior in the contexts of social behavior, risk taking and health care. We find that framing matters for people’s assessment of the benefits of NPIs. In two commonly used frames, most subjects in our experiment drastically underestimate the number of cases NPIs avoid. Framing growth in terms of doubling times, rather than growth rates, reduces bias. When the scenario is framed in terms of time gained, rather than cases avoided, the median subject assesses the benefit of NPIs correctly. These findings suggest changes that public health authorities can adopt to better communicate the exponential spread of infectious diseases.
Synchronised inflations generate greater gravity dependent lung ventilation in neonates
Authors: Dowse G , Perkins E , Thomson J , Schinckel N , Pereira-Fantini PM , Tingay DG
Published: June 2020

Objective

Synchronising positive pressure inflations with an infant’s own breathing is considered lung protective, but the ventilation patterns within the infant lung during synchronous and asynchronous inflations are unknown. The aim of this study was to describe the regional distribution patterns of tidal ventilation within the lung during mechanical ventilation that is synchronous or asynchronous with an infant’s own breathing effort.

Methods

Intubated infants receiving synchronised mechanical ventilation at The Royal Children’s Hospital NICU were studied. During four 10-minute periods of routine care, regional distribution of tidal volume (VT; Electrical Impedance Tomography), delivered pressure and airway flow (Florian Respiratory Monitor) were measured for every inflation. Post hoc, each inflation was then classified as synchronous or asynchronous from video data of the ventilator screen, and the distribution of absolute VT and delivered ventilation characteristics determined.

Results

2749 inflations (2462 synchronous) were analysed in 19 infants; mean (SD) age 28 (30) day, GA 35 (5) weeks. Synchronous inflations were associated with a shorter respiratory cycle (p=0.004) and more homogenous VT (centre of ventilation) along the right (0%) to left (100%) lung plane; 45.3 (8.6)% vs 48.8 (9.4)% (uniform ventilation 46%). The gravity dependent centre of ventilation was a mean (95% CI) 2.1 (−0.5, 4.6)% more towards the dependent lung during synchronous inflations. Tidal ventilation relative to anatomical lung size was more homogenous during synchronised inflations in the dependent lung.

Conclusion

Synchronous mechanical ventilator lung inflations generate more gravity dependent lung ventilation and more uniform right to left ventilation than asynchronous inflations.
A discrete-time-evolution model to forecast progress of Covid-19 outbreak
Authors: Curado Evaldo M. F. , Curado Marco R.
Published: June 2020

Based on well-known infection models, we constructed a new model to forecast the propagation of the Covid-19 pandemic which yields a discrete-time evolution with one day interval. The proposed model can be easily implemented with daily updated data sets of the pandemic publicly available by many sources. It has only two adjustable parameters and is able to predict the evolution of the total number of infected people in a country for the next 14 days, if parameters do not change during this time. The model incorporates the main aspects of the disease such as the the fact that there are asymptomatic and symptomatic phases (both capable of propagating the virus), and that these phases take almost two weeks before the infected person status evolves to the next (asymptomatic becomes symptomatic or symptomatic becomes either recovered or dead). One advantage of the model is that it gives directly the number of total infected people in each day (in thousands, tens of thousands or hundred of thousands). The model was tested with data from Brazil, UK and South Korea, it predicts quite well the evolution of the disease and therefore may be a useful tool to estimate the propagation of the disease.
Combining segmental bulk- and single-cell RNA-sequencing to define the chondrocyte gene expression signature in the murine knee joint
Authors: Sunkara Vikram , Heinz Gitta A. , Heinrich Frederik F. , Durek Pawel , Mobasheri Ali , Mashreghi Mir-Farzin , Lang Annemarie
Published: June 2020

Objective

Due to the small size of the murine knee joint, extracting the chondrocyte transcriptome from articular cartilage (AC) is a major technical challenge. In this study, we demonstrate a new and pragmatic approach of combining bulk RNA-sequencing (RNA-seq) and single cell (sc)RNA-seq to address this problem.

Design

We propose a new cutting strategy of the murine femur which produces three segments with a predictable mixed cell populations, where one segment contains AC and growth plate (GP) chondrocytes, another contains GP chondrocytes, and the last segment contains only bone and bone marrow. We analysed the bulk RNA-seq of the different segments to find common and distinct genes between the segments. Then, the segment containing AC chondrocytes was digested and analysed via scRNA-seq.

Results

Differential expression analysis using bulk RNA-seq identified 350 candidate chondrocyte gene in the AC segment. Gene set enrichment analysis of these genes revealed biological processes related- and non-related to chondrocytes, including, cartilage development (adj. p-value: 3.45E-17) and endochondral bone growth (adj. p-value 1.22E-4), respectively. ScRNA-seq of the AC segment found a cluster of 131 cells containing mainly chondrocytes. This cluster had 759 differentially expressed genes which enriched for extracellular matrix organisation (adj. p-value 7.76E-40) and other joint development processes. The intersection of the gene sets of bulk- and scRNA-seq contained 75 genes, where all but ten genes were previously implicated in cartilage homeostasis or osteoarthritis (OA) progression.

Conclusions

Our approach has the potential to detect the scarce disease phenotypes of chondrocytes in murine OA models.
Protein Profiles: Biases and Protocols
Authors: Urban Gregor , Torrisi Mirko , Magnan Christophe N. , Pollastri Gianluca , Baldi Pierre
Published: June 2020

The use of evolutionary profiles to predict protein secondary structure, as well as other protein structural features, has been standard practice since the 1990s. Using profiles in the input of such predictors, in place or in addition to the sequence itself, leads to significantly more accurate predictors. While profiles can enhance structural signals, their role remains somewhat surprising as proteins do not use profiles when folding in vivo. Furthermore, the same sequence-based redundancy reduction protocols initially derived to train and evaluate sequence-based predictors, have been applied to train and evaluate profile-based predictors. This can lead to unfair comparisons since profile may facilitate the bleeding of information between training and test sets. Here we use the extensively studied problem of secondary structure prediction to better evaluate the role of profiles and show that: (1) high levels of profile similarity between training and test proteins are observed when using standard sequence-based redundancy protocols; (2) the gain in accuracy for profile-based predictors, over sequence-based predictors, strongly relies on these high levels of profile similarity between training and test proteins; and (3) the overall accuracy of a profile-based predictor on a given protein dataset provides abiasedmeasure when trying to estimate the actual accuracy of the predictor, or when comparing it to other predictors. We show, however, that this bias can be avoided by implementing a new protocol (EVALpro) which evaluates the accuracy of profile-based predictors as a function of the profile similarity between training and test proteins. Such a protocol not only allows for a fair comparison of the predictors on equally hard or easy examples, but also completely removes the need for selecting arbitrary similarity cutoffs when selecting test proteins. The EVALpro program is available for download from the SCRATCH suite (http://scratch.proteomics.ics.uci.edu).
MAGI1 inhibits the AMOTL2/p38 stress pathway and prevents luminal breast tumorigenesis
Authors: Kantar Diala , Mur Emilie Bousquet , Mancini Maicol , Slaninova Vera , Salah Yezza Ben , Costa Luca , Forest Elodie , Lassus Patrice , Géminard Charles , Boissière-Michot Florence , Orsetti Béatrice , Theillet Charles , Colinge Jacques , Benistant Christine , Maraver Antonio , Heron-Milhavet Lisa , Djiane Alexandre
Published: June 2020

Alterations to cell polarization or to intercellular junctions are often associated with epithelial cancer progression, including breast cancers (BCa). We show here that the loss of the junctional scaffold protein MAGI1 is associated with bad prognosis in luminal BCa, and promotes tumorigenesis. E-cadherin and the actin binding scaffold AMOTL2 accumulate inMAGI1deficient cells which are subjected to increased stiffness. These alterations are associated with low YAP activity, the terminal Hippo-pathway effector, but with an elevated ROCK and p38 Stress Activated Protein Kinase activities. Blocking ROCK prevented p38 activation, suggesting that MAGI1 limits p38 activity in part through releasing actin strength. Importantly, the increased tumorigenicity ofMAGI1deficient cells is rescued in the absence of AMOTL2 or after inhibition of p38, demonstrating that MAGI1 acts as a tumor-suppressor in luminal BCa by inhibiting an AMOTL2/p38 stress pathway.
Managing mixed stands can mitigate severe climate change impacts on ecosystem functioning
Authors: Jourdan M. , Cordonnier T. , Dreyfus P. , Riond C. , de Coligny F. , Morin X.
Published: June 2020

Climate change affects forest ecosystem processes and related services due to increasing temperature and increasing extreme drought event frequency. This effect can be direct through the alteration of the physiological responses of trees, but also indirect, by modifying interactions between trees and thus changing communities’ composition. Such changes might affect species richness with high impacts on ecosystem functioning, especially productivity.

Regarding management issues, mixed stands are usually considered a good option to maintain forest cover and ecosystem services under climate change. However, the possibility to maintain these mixed stands with management actions with positive effects on forest functioning under climate change remains uncertain and deserves further investigations. Relying on a simulation-based study with a forest gap model, we thus addressed the following questions: (1) Are monospecific stands vulnerable to climate change? (2) Would mixed stands significantly mitigate climate change effects on forest productivity and wood production under climate change? (3) Would conversion to mixed stand management affect significantly forest productivity and wood production under climate change compare to monospecific management?

With a 150 years simulation approach, we quantified potential climate change effect (using RCP 8.5) compared to present climate and managements effect in the French Alps, focusing on five tree species. The gap-model we used included a management module, which allowed testing six silvicultural scenarios on different stands, with various composition, structure or environmental conditions, under climate change.

These simulations showed that monospecific stands currently growing in stressful conditions would be too vulnerable to climate change to be maintained. Managing mixed stands or conversion from pure to mixed stands would make it possible to maintain higher productivity in the long-term than monospecific stands, even under severe climate change. This pattern depends to species and sites considered. Our results will feed into discussion on forest management in the context of climate change.
AC. elegansmodel ofC9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation
Authors: Sonobe Yoshifumi , Aburas Jihad , Islam Priota , Gendron Tania F. , Brown André E.X. , Roos Raymond P. , Kratsios Paschalis
Published: June 2020

A hexanucleotide repeat expansion GGGGCC in the noncoding region ofC9orf72is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Potentially toxic dipeptide repeats (DPRs) are synthesized from the GGGGCC sequence via repeat associated non-AUG (RAN) translation. We developedC. elegansmodels that express, either ubiquitously or exclusively in neurons, a transgene with 75 GGGGCC repeats flanked by intronicC9orf72sequence. The worms generate DPRs (poly-glycine-alanine [poly-GA], poly-glycine-proline [poly-GP]) and display neurodegeneration, locomotor and lifespan defects. Mutation of a non-canonical translation-initiating codon (CUG) upstream of the repeats blocked poly-GA production and ameliorated disease, suggesting poly-GA is pathogenic. Importantly, eukaryotic translation initiation factor 2D (eif-2D/eIF2D) was necessary for RAN translation. Genetic removal ofeif-2Dincreased lifespan in bothC. elegansmodels.In vitrofindings in human cells demonstrated a conserved role foreif-2D/eIF2Din RAN translation that could be exploited for ALS and FTD therapy.
Contextual experience modifies functional connectome indices of topological strength and organization
Authors: Pompilus Marjory , Colon-Perez Luis M. , Grudny Matteo M. , Febo Marcelo
Published: June 2020

Stimuli presented at short temporal delays before functional magnetic resonance imaging (fMRI) can have a robust impact on the organization of synchronous activity in resting state networks. This presents an opportunity to investigate how sensory, affective and cognitive stimuli alter functional connectivity in rodent models. In the present study, we assessed the effect of a familiar contextual stimulus presented 10 minutes prior to sedation for imaging on functional connectivity. A subset of animals were co-presented with an unfamiliar social stimulus in the same environment to further investigate the effect of familiarity on network topology. Female and male rats were imaged at 11.1 Tesla and graph theory analysis was applied to matrices generated from seed-based functional connectivity data sets with 144 brain regions (nodes) and 10,152 pairwise correlations (edges). Our results show an unconventional network topology in response to the familiar (context) but not the unfamiliar (social) stimulus. The familiar stimulus strongly reduced network strength, global efficiency, and altered the location of the highest eigenvector centrality nodes from cortex to the hypothalamus. We did not observe changes in modular organization, nodal cartographic assignments, assortative mixing, rich club organization, and network resilience. The results suggest that experiential factors, perhaps involving associative or episodic memory, can exert a dramatic effect on functional network strength and efficiency when presented at a short temporal delay before imaging.
The transcription factor STAT5 binds to distinct super-enhancer sites and controlsLrrc32expression in a prominent autoimmune and allergic disease risk locus
Authors: Hennighausen Lothar , Lee Hye Kyung
Published: June 2020

Genetic variants associated with diseases are enriched in genomic sequences linked to regulatory regions, such as enhancers, super-enhancers and possibly repressors, that control nearby and distant genes. A known allergic and autoimmune risk locus at chromosome 11q13.51,2is associated with theLRRC32gene, which encodes GARP, a protein critical for TGF-β delivery3. This region coincides with a candidate enhancer that was predicted by the presence of activating chromatin marks and contains a polymorphism significantly associated with GARP expression on CD4+CD127-CD25+Tregcells4. In the mouse, binding of the cytokine-induced transcription factor STAT5 was detected at two sites within the expansive candidate enhancer region and a 2.3 kb deletion resulted in reducedLrrc32expression4. However, a clear definition of the enhancer units controlled by STAT5 and a functional understanding of STAT5 in the regulation ofLrrc32are needed. Here we use high-resolution ChIP-seq and identify three STAT5 binding sites within theLrrc32super-enhancer, one shared between Tregcells and mammary epithelium and one specific to each respective cell type. Using mice that express only 10% of normal STAT5 levels we demonstrate the defining contribution of STAT5 in the activation of theLrrc32super-enhancer.
Trade-offs and design principles in the spatial organization of catalytic particles
Authors: Hinzpeter Florian , Tostevin Filipe , Buchner Alexander , Gerland Ulrich
Published: June 2020

Spatial organization of catalytic particles is ubiquitous in biological systems across different length scales, from enzyme complexes to metabolically coupled cells. Despite the different scales, these systems share common features of localized reactions with partially hindered diffusive transport, determined by the collective arrangement of the catalysts. Yet it remains largely unexplored how different arrangements affect the interplay between the reaction and transport dynamics, which ultimately determines the flux through the reaction pathway. Here we show that two fundamental trade-offs arise, the first between efficient inter-catalyst transport and depletion of substrate, and the second between steric confinement of intermediate products and accessibility of catalysts to substrate. We use a model reaction pathway to characterize the general design principles for the arrangement of catalysts that emerge from the interplay of these trade-offs. We find that the question of optimal catalyst arrangements generalizes the famous Thomson problem of electrostatics.
Metal-Organic Framework Encapsulated Whole-Cell Vaccines Enhance Humoral Immunity against Bacterial Infection
Authors: Luzuriaga Michael A. , Herbert Fabian C. , Brohlin Olivia R. , Gadhvi Jashkaran , Howlett Thomas , Shahrivarkevishahi Arezoo , Wijesundara Yalini H. , Venkitapathi Sundharamani , Veera Kavya , Ehrman Ryanne , Benjamin Candace E. , Popal Sarah , Burton Michael D. , Ingersoll Molly A. , De Nisco Nicole J. , Gassensmith Jeremiah J.
Published: June 2020

The increasing rate of resistance of bacterial infection against antibiotics requires next generation approaches to fight potential pandemic spread. The development of vaccines against pathogenic bacteria has been difficult owing, in part, to the genetic diversity of bacteria. Hence, there are many potential target antigens and littlea prioriknowledge of which antigen/s will elicit protective immunity. The painstaking process of selecting appropriate antigens could be avoided with whole-cell bacteria; however, whole-cell formulations typically fail to produce long-term and durable immune responses. These complications are one reason why no vaccine against any type of pathogenicE. colihas been successfully clinically translated. As a proof of principle, we demonstrate a method to enhance the immunogenicity of a model pathogenicE. colistrain by forming a slow releasing depot. TheE. colistrain CFT073 was biomimetically mineralized within a metal-organic framework (MOF). This process encapsulates the bacteria within 30 minutes in water and at ambient temperatures. Vaccination with this new formulation substantially enhances antibody production and results in significantly enhanced survival in a mouse model of bacteremia compared to standard inactivated formulations.
Ionophore antibiotic X-206 is a potent and selective inhibitor of SARS-CoV-2 infectionin vitro
Authors: Svenningsen Esben B. , Thyrsted Jacob , Blay-Cadanet Julia , Liu Han , Lin Shaoquan , Villameriel Jaime Moyano , Olagnier David , Idorn Manja , Paludan Søren R. , Holm Christian K. , Poulsen Thomas B.
Published: June 2020

Pandemic spread of emerging human pathogenic viruses such as the current SARS-CoV-2, poses both an immediate and future challenge to human health and society. Currently, effective treatment of infection with SARS-CoV-2 is limited and broad spectrum antiviral therapies to meet other emerging pandemics are absent leaving the World population largely unprotected. Here, we have identified distinct members of the family of polyether ionophore antibiotics with potent ability to inhibit SARS-CoV-2 replication and cytopathogenicity in cells. Several compounds from this class displayed more than 100-fold selectivity between viral-induced cytopathogenicity and inhibition of cell viability, however the compound X-206 displayed >500-fold selectivity and was furthermore able to inhibit viral replication even at sub-nM levels. The antiviral mechanism of the polyether ionophores is currently not understood in detail. We demonstrate, through unbiased bioactivity profiling, that their effects on the host cells differ from those of cationic amphiphiles such as hydroxychloroquine. Collectively, our data suggest that polyether ionophore antibiotics should be subject to further investigations as potential broad-spectrum antiviral agents.
3D microarchitecture of the human tuberculous granuloma
Authors: Wells Gordon , Glasgow Joel N. , Nargan Kievershen , Lumamba Kapongo , Madansein Rajhmun , Maharaj Kameel , Hunter Robert L. , Naidoo Threnesan , Ramdial Pratista , Coetzer Llelani , le Roux Stephan , du Plessis Anton , Steyn Adrie J.C.
Published: June 2020

Our current understanding of the pathophysiology of human pulmonary TB is limited by the paucity of human TB lung tissue for study and reliance on 2D analytical methods. Here, to overcome the limitations of conventional 2D histopathology, we used high-resolution 3D X-ray imaging (µCT/nCT) to characterize necrotic lesions within human tuberculous lung tissues in relation to the airways and vasculature. We observed marked heterogeneity in the 3D structure and volume of lesions. Also, 3D imaging of large human TB lung sections provides unanticipated new insight into the spatial organization of TB lesions in relation to airways and the vascular system. Contrary to the current dogma depicting granulomas as simple spherical structures, we show that TB lesions exhibit complex, cylindrical, branched-type morphologies, which are connected to, and shaped by, the small airways. Our results highlight the likelihood that a single structurally complex lesion could be wrongly viewed as multiple independent lesions when evaluated in 2D. These findings have strong implications for understanding the pathophysiology and evolution of TB disease and suggest that aerosolized drug delivery strategies for TB should be reconsidered.
The changing mouse embryo transcriptome at whole tissue and single-cell resolution
Authors: He Peng , Williams Brian A. , Trout Diane , Marinov Georgi K. , Amrhein Henry , Berghella Libera , Goh Say-Tar , Plajzer-Frick Ingrid , Afzal Veena , Pennacchio Len A. , Dickel Diane E. , Visel Axel , Ren Bing , Hardison Ross C. , Zhang Yu , Wold Barbara J.
Published: June 2020

In mammalian embryogenesis differential gene expression gradually builds the identity and complexity of each tissue and organ system. We systematically quantified mouse polyA-RNA from embryo day E10.5 to birth, sampling 17 whole tissues, enhanced with single-cell measurements for the developing limb. The resulting developmental transcriptome is globally structured by dynamic cytodifferentiation, body-axis and cell-proliferation gene sets, characterized by their promoters’ transcription factor (TF) motif codes. We decomposed the tissue-level transcriptome using scRNA-seq and found that neurogenesis and haematopoiesis dominate at both the gene and cellular levels, jointly accounting for 1/3 of differential gene expression and over 40% of identified cell types. Integrating promoter sequence motifs with companion ENCODE epigenomic profiles identified a promoter de-repression mechanism unique to neuronal expression clusters and attributable to known and novel repressors. Focusing on the developing limb, scRNA-seq identified 25 known and candidate novel cell types, including progenitor and differentiating states with computationally inferred lineage relationships. We extracted cell type TF networks and complementary sets of candidate enhancer elements by de-convolving whole-tissue IDEAS epigenome chromatin state models. These ENCODE reference data, computed network components and IDEAS chromatin segmentations, are companion resources to the matching epigenomic developmental matrix, available for researchers to further mine and integrate.
Improving representations of genomic sequence motifs in convolutional networks with exponential activations
Authors: Koo Peter K. , Ploenzke Matt
Published: June 2020

Deep convolutional neural networks (CNNs) trained on regulatory genomic sequences tend to build representations in a distributed manner, making it a challenge to extract learned features that are biologically meaningful, such as sequence motifs. Here we perform a comprehensive analysis on synthetic sequences to investigate the role that CNN activations have on model interpretability. We show that employing an exponential activation to first layer filters consistently leads to interpretable and robust representations of motifs compared to other commonly used activations. Strikingly, we demonstrate that CNNs with better test performance do not necessarily imply more interpretable representations with attribution methods. We find that CNNs with exponential activations significantly improve the efficacy of recovering biologically meaningful representations with attribution methods. We demonstrate these results generalise to real DNA sequences across severalin vivodatasets. Together, this work demonstrates how a small modification to existing CNNs, i.e. setting exponential activations in the first layer, can significantly improve the robustness and interpretabilty of learned representations directly in convolutional filters and indirectly with attribution methods.
Transcriptional networks are dynamically regulated during cell cycle progression in human Pluripotent Stem Cells
Authors: Osnato Anna , Brown Stephanie , Vallier Ludovic
Published: June 2020

Cell cycle progression follows a precise sequence of events marked by different phases and checkpoints which are associated with specific chromatin organisation. Whilst these changes have been extensively studied, their consequences on transcriptional networks remain to be fully uncovered, especially in dynamic model systems such as stem cells. Here, we take advantage of the FUCCI reporter system to show that chromatin accessibility, gene expression and key transcription factors binding change during cell cycle progression in human Embryonic Stem Cells (hESCs). These analyses reveal that core pluripotency factors such as OCT4, NANOG and SOX2 but also chromatin remodelers such as CTCF and RING1B bind the genome at specific phases of the cell cycle. Importantly, this binding pattern allows differentiation in the G1 phase while preserving pluripotency in the S/G2/M. Our results highlight the importance of studying transcriptional and epigenetic regulations in the dynamic context of the cell cycle.
Global epistasis emerges from a generic model of a complex trait
Authors: Reddy Gautam , Desai Michael M.
Published: June 2020

Epistasis between mutations can make adaptation contingent on evolutionary history. Yet despite widespread “microscopic” epistasis between the mutations involved, microbial evolution experiments show consistent patterns of fitness increase between replicate lines. Recent work shows that this consistency is driven in part by global patterns of diminishing-returns and increasing-costs epistasis, which make mutations systematically less beneficial (or more deleterious) on fitter genetic backgrounds. However, the mechanistic basis of this “global” epistasis remains unknown. Here we show that diminishing-returns and increasing-costs epistasis emerge generically as a consequence of pervasive microscopic epistasis. Our model predicts a specific quantitative relationship between the magnitude of global epistasis and the stochastic effects of microscopic epistasis, which we confirm by re-analyzing existing data. We further show that the distribution of fitness effects takes on a universal form when epistasis is widespread, and introduce a novel fitness landscape model to show how phenotypic evolution can be repeatable despite sequence-level stochasticity.
Why do we retrace our visual steps? Semantic and episodic memory in gaze reinstatement
Authors: Ramey Michelle M. , Yonelinas Andrew P. , Henderson John M.
Published: June 2020

When we look at repeated scenes, we tend to visit similar regions each time—a phenomenon known as resampling. Resampling has long been attributed to episodic memory, but the relationship between resampling and episodic memory has recently been found to be less consistent than assumed. A possibility that has yet to be fully considered is that factors unrelated to episodic memory may generate resampling: for example, other factors such as semantic memory and visual salience that are consistently present each time an image is viewed and are independent of specific prior viewing instances. We addressed this possibility by tracking participants’ eyes during scene viewing to examine how semantic memory, indexed by the semantic informativeness of scene regions (i.e., meaning), is involved in resampling. We found that viewing more meaningful regions predicted resampling, as did episodic familiarity strength. Furthermore, we found that meaning interacted with familiarity strength to predict resampling. Specifically, the effect of meaning on resampling was attenuated in the presence of strong episodic memory, and vice versa. These results suggest that episodic and semantic memory are each involved in resampling behavior and are in competition rather than synergistically increasing resampling. More generally, this suggests that episodic and semantic memory may compete to guide attention.
Influences on memory for naturalistic visual episodes: sleep, familiarity, and traits differentially affect forms of recall
Authors: Coutanche Marc N. , Koch Griffin E. , Paulus John P.
Published: June 2020

The memories we form are composed of information that we extract from multifaceted episodes. Static stimuli and paired associations have proven invaluable stimuli for understanding memory, but real-life events feature spatial and temporal dimensions that help form new retrieval paths. We ask how the ability to recall semantic, temporal, and spatial aspects (the “what, when, and where”) of naturalistic episodes is affected by three influences—prior familiarity, postencoding sleep, and individual differences—by testing their influence on three forms of recall: cued recall, free recall, and the extent that recalled details are recombined for a novel prompt. Naturalistic videos of events with rare animals were presented to 115 participants, randomly assigned to receive a 12- or 24-h delay with sleep and/or wakefulness. Participants’ immediate and delayed recall was tested and coded by its spatial, temporal, and semantic content. We find that prior familiarity with items featured in events improved cued recall, but not free recall, particularly for temporal and spatial details. In contrast, postencoding sleep, relative to wakefulness, improved free recall, but not cued recall, of all forms of content. Finally, individuals with higher trait scores in the Survey of Autobiographical Memory spontaneously incorporated more spatial details during free recall, and more event details (at a trend level) in a novel recombination recall task. These findings show that prior familiarity, postencoding sleep, and memory traits can each enhance a different form of recall. More broadly, this work highlights that recall is heterogeneous in response to different influences on memory.
Similar time course of fast familiarity and slow recollection processes for recognition memory in humans and macaques
Authors: Wu Zhemeng , Kavanova Martina , Hickman Lydia , Lin Fiona , Buckley Mark J.
Published: June 2020

According to dual-process theory, recognition memory performance draws upon two processes, familiarity and recollection. The relative contribution to recognition memory are commonly distinguished in humans by analyzing receiver-operating-characteristics (ROC) curves; analogous methods are more complex and very rare in animals but fast familiarity and slow recollective-like processes (FF/SR) have been detected in nonhuman primates (NHPs) based on analyzing recognition error response time profiles. The relative utility of these methods to investigate familiarity and recollection/recollection-like processes across species is uncertain; indeed, even how comparable the FF/SR measures are across humans and NHPs remains unclear. Therefore, in this study a broadly similar recognition memory task was exploited in both humans and a NHP to investigate the time course of the two recognition processes. We first show that the FF/SR dissociation exists in this task in human participants and then we demonstrate a similar profile in the NHP which suggests that FF/SR processes are comparable across species. We then verified, using ROC-derived indices for each time-bin in the FF/SR profile, that the ROC and FF/SR measures are related. Hence, we argue that the FF/SR approach, procedurally easier in nonhuman animals, can be used as a decent proxy to investigate these two recognition processes in future animal studies, important given that scant data exists as to the neural basis underlying recollection yet many of the most informative techniques primarily exist in animal models.
Reducing shock imminence eliminates poor avoidance in rats
Authors: Laughlin Lindsay C. , Moloney Danielle M. , Samels Shanna B. , Sears Robert M. , Cain Christopher K.
Published: June 2020

In signaled active avoidance (SigAA), rats learn to suppress Pavlovian freezing and emit actions to remove threats and prevent footshocks. SigAA is critical for understanding aversively motivated instrumental behavior and anxiety-related active coping. However, with standard protocols ∼25% of rats exhibit high freezing and poor avoidance. This has dampened enthusiasm for the paradigm and stalled progress. We demonstrate that reducing shock imminence with long-duration warning signals leads to greater freezing suppression and perfect avoidance in all subjects. This suggests that instrumental SigAA mechanisms evolved to cope with distant harm and protocols that promote inflexible Pavlovian reactions are poorly designed to study avoidance.