bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxytocin signals via Gi and Gq to drive persistent CA2 pyramidal cell firing and strengthen CA3-CA1 neurotransmission
Authors: Eyring Katherine W. , Liu Jingjing , König Gabriele M. , Hidema Shizu , Nishimori Katsuhiko , Kostenis Evi , Tsien Richard W.
Published: May 2020

The oxytocin receptor (OXTR) is concentrated in specific brain regions, exemplified by hippocampal subregion CA2, that support social information processing. Oxytocinergic modulation of CA2 directly affects social behavior, yet how oxytocin regulates activity in CA2 remains incompletely understood. We found that OXTR stimulation acts via closure of M-current potassium channels in all OXT-sensitive CA2 neurons. M-current inhibition was persistent in CA2 pyramidal cells, whose prolonged burst firing required functional coupling of the OXTR to both Gαq and Gαi proteins. Other neuromodulators acted via distinct patterns of G-protein signaling to induce CA2 pyramidal neuron burst firing, underscoring its likely importance. CA2 burst firing impacted hippocampal subregion CA1 wherestratum oriens-resident CA1 interneurons were targeted more strongly than CA1 pyramidal cells. Oxytocinergic modulation of interneurons, via CA2 pyramidal cell input and directly, triggered a long-lasting enhancement of CA3-CA1 transmission. Thus, transient activation of oxytocinergic inputs may initiate long-lasting recording of social information.
Diverse deep neural networks all predict human IT well, after training and fitting
Authors: Storrs Katherine R. , Kietzmann Tim C. , Walther Alexander , Mehrer Johannes , Kriegeskorte Nikolaus
Published: May 2020

Deep neural networks (DNNs) trained on object recognition provide the best current models of high-level visual areas in the brain. What remains unclear is how strongly network design choices, such as architecture, task training, and subsequent fitting to brain data contribute to the observed similarities. Here we compare a diverse set of nine DNN architectures on their ability to explain the representational geometry of 62 isolated object images in human inferior temporal (hIT) cortex, as measured with functional magnetic resonance imaging. We compare untrained networks to their task-trained counterparts, and assess the effect of fitting them to hIT using a cross-validation procedure. To best explain hIT, we fit a weighted combination of the principal components of the features within each layer, and subsequently a weighted combination of layers. We test all models across all stages of training and fitting for their correlation with the hIT representational dissimilarity matrix (RDM) using an independent set of images and subjects. We find that trained models significantly outperform untrained models (accounting for 57% more of the explainable variance), suggesting that features representing natural images are important for explaining hIT. Model fitting further improves the alignment of DNN and hIT representations (by 124%), suggesting that the relative prevalence of different features in hIT does not readily emerge from the particular ImageNet object-recognition task used to train the networks. Finally, all DNN architectures tested achieved equivalent high performance once trained and fitted. Similar ability to explain hIT representations appears to be shared among deep feedforward hierarchies of nonlinear features with spatially restricted receptive fields.
Robust decomposition of cell type mixtures in spatial transcriptomics
Authors: Cable Dylan M. , Murray Evan , Zou Luli S. , Goeva Aleksandrina , Macosko Evan Z. , Chen Fei , Irizarry Rafael A.
Published: May 2020

Spatial transcriptomic technologies measure gene expression at increasing spatial resolution, approaching individual cells. However, a limitation of current technologies is that spatial measurements may contain contributions from multiple cells, hindering the discovery of cell type-specific spatial patterns of localization and expression. Here, we develop Robust Cell Type Decomposition (RCTD,https://github.com/dmcable/RCTD), a computational method that leverages cell type profiles learned from single-cell RNA sequencing data to decompose mixtures, such as those observed in spatial transcriptomic technologies. Our approach accounts for platform effects introduced by systematic technical variability inherent to different sequencing modalities. We demonstrate RCTD provides substantial improvement in cell type assignment in Slide-seq data by accurately reproducing known cell type and subtype localization patterns in the cerebellum and hippocampus. We further show the advantages of RCTD by its ability to detect mixtures and identify cell types on an assessment dataset. Finally, we show how RCTD’s recovery of cell type localization uniquely enables the discovery of genes within a cell type whose expression depends on spatial environment. Spatial mapping of cell types with RCTD has the potential to enable the definition of spatial components of cellular identity, uncovering new principles of cellular organization in biological tissue.
Screening for Potential Interaction Partners with Surface Plasmon Resonance Imaging Coupled to MALDI Mass Spectrometry
Authors: Anders Ulrike , Gulotti-Georgieva Maya , Zelger-Paulus Susann , Hibti Fatima-Ezzahra , Frydman Chiraz , Suckau Detlev , Sigel Roland K.O. , Zenobi Renato
Published: May 2020

We coupled SPR imaging (SPRi) with matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) to identify new potential RNA binders. Here, we improve this powerful method, especially by optimizing the proteolytic digestion (type of reducing agent, its concentration, and incubation time), to work with complex mixtures, specifically a lysate of the rough mitochondrial fraction from yeast. The advantages of this hyphenated method compared to column-based or separate analyses are (i) rapid and direct visual readout from the SPRi array, (ii) possibility of high-throughput analysis of different interactions in parallel, (iii) high sensitivity, and (iv) no sample loss or contamination due to elution or micro-recovery procedures. The model system used is a catalytically active RNA (group IIB intron fromSaccharomyces cerevisiae, Sc.ai5γ) and its cofactor Mss116. The protein supports the RNA folding process and thereby the subsequent excision of the intronic RNA from the coding part. Using the novel approach of coupling SPR with MALDI MS, we report the identification of potential RNA-binding proteins from a crude yeast mitochondrial lysate in a non-targeted approach. Our results show that proteins other than the well-known cofactor Mss116 interact withSc.ai5γ (Dbp8, Prp8, Mrp13, and Cullin-3), suggesting that the intron folding and splicing are regulated by more than one cofactorin vivo.

Graphical abstract

Author contribution

Ulrike Anders and Maya Gulotti-Georgieva contributed equally to this work.
U-shape short-range extrinsic connectivity organisation around the human central sulcus
Authors: Pron Alexandre , Deruelle Christine , Coulon Olivier
Published: May 2020

The central sulcus is probably one of the most studied folds in the human brain, owing to its clear relationship with primary sensory-motor functional areas. However, due to the difficulty of estimating the trajectories of the U-shape fibres from diffusion MRI, the short structural connectivity of this sulcus remains relatively unknown. In this context, we studied the spatial organization of these U-shape fibres along the central sulcus. Based on high quality diffusion MRI data of 100 right-handed subjects and state-of-the-art pre-processing pipeline, we first define a connectivity space that provide a comprehensive and continuous description of the short-range anatomical connectivity around the central sulcus at both the individual and group levels. We then infer the presence of five major U-shape fibre bundles at the group level in both hemispheres by applying unsupervised clustering in the connectivity space. We propose a quantitative investigation of their position and number of streamlines as a function of phenotypic traits such as sex and hemispheres and functional scores such as handedness and manual dexterity. Main findings of this study are twofold: a description of U-shape short-range connectivity along the central sulcus at group level and the evidence of a significant relationship between the position of three hand related U-shape fibre bundles and the handedness score of subjects.
A kinetic ensemble of the Alzheimer’s Aβ peptide
Authors: Löhr Thomas , Kohlhoff Kai , Heller Gabriella T. , Camilloni Carlo , Vendruscolo Michele
Published: May 2020

The discovery that disordered proteins are widespread in the human proteome has prompted the quest for methods to characterize the conformational properties that determine their functional and dysfunctional behaviour. It has become customary to describe these proteins in terms of structural ensembles and free energy landscapes, which offer conformational and thermodynamic insight. However, a current major challenge is to generalize this description to ‘kinetic ensembles’, thereby also providing information on transition rates between states. Approaches based on the theory of stochastic processes can be particularly suitable for this purpose. Here, we develop a Markov state model and illustrate its application by determining a kinetic ensemble of the 42-residue form of the amyloid-β peptide (Aβ42), whose aggregation is associated with Alzheimer’s disease. Using the Google Compute Engine, we generated 315 μs all-atom, explicit solvent molecular dynamics trajectories, validated with experimental data from nuclear magnetic resonance spectroscopy. Using a probabilistic-based definition of conformational states in a neural network approach, we found that Aβ42 is characterized by inter-state transitions no longer than the microsecond timescale, exhibiting only fully unfolded or short-lived, partially-folded states. We contextualize our findings by performing additional simulations of the oxidized form of Aβ42. Our results illustrate how the use of kinetic ensembles offers an effective means to provide information about the structure, thermodynamics, and kinetics of disordered proteins towards an understanding of these ubiquitous biomolecules.
A two-trick pony: lysosomal protease cathepsin B possesses surprising ligase activity
Authors: Lambeth Tyler R. , Dai Zhefu , Zhang Yong , Julian Ryan R.
Published: May 2020

Cathepsin B is an important protease within the lysosome, where it helps recycle proteins to maintain proteostasis. It is also known to degrade proteins elsewhere but has no other known functionality. However, by carefully monitoring peptide digestion with liquid chromatography and mass spectrometry, we observed synthesis of novel peptides during cathepsin B incubations. This ligation activity was explored further with a variety of peptide substrates to establish mechanistic details and was found to operate through a two-step mechanism with proteolysis and ligation occurring separately. Further explorations using varied sequences indicated increased affinity for some substrates, though all were found to ligate to some extent. Finally, experiments with a proteolytically inactive form of the enzyme yielded no ligation, indicating that the ligation reaction occurs in the same active site but in the reverse direction of proteolysis. These results clearly establish that cathepsin B can act as both a protease and ligase, although protease action eventually dominates over longer periods of time.
Immunization withMycobacterium vaccaeNCTC 11659 prevents the development of PTSD-like sleep and behavioral phenotypes after sleep disruption and acute stress in mice
Authors: Bowers Samuel J. , Lambert Sophie , He Shannon , Lowry Christopher A. , Fleshner Monika , Wright Kenneth P. , Turek Fred W. , Vitaterna Martha H.
Published: May 2020

Because regular sleep disruption can increase vulnerability to stress-related psychiatric disorders, there is a need to explore novel countermeasures to increase stress resilience after inadequate sleep. In this study, we explored the impact of 5 days of intermittent sleep disruption on vulnerability to acute social defeat stress in mice, and investigated the ability of the environmental, immunomodulatory bacteriumMycobacterium vaccaeNCTC 11659 (MV) to promote stress resilience in that context. We found that mice receiving sleep disruption plus acute stress developed sleep and behavioral phenotypes that had some features of human posttraumatic stress disorder (PTSD) including reduced NREM delta power and increased NREM beta power in post-stress sleep EEG, persistent increases in sleep fragmentation and the REM:Sleep ratio, and behavioral changes. Importantly, immunization with heat-killed MV prevented the development of this phenotype. These results support further research into novel, microbial-based countermeasures to improve health and increase resilience to sleep disruption.
Reversing age: dual species measurement of epigenetic age with a single clock
Authors: Horvath Steve , Singh Kavita , Raj Ken , Khairnar Shraddha , Sanghavi Akshay , Shrivastava Agnivesh , Zoller Joseph A. , Li Caesar Z. , Herenu Claudia B. , Canatelli-Mallat Martina , Lehmann Marianne , Solberg Woods Leah C. , Martinez Angel Garcia , Wang Tengfei , Chiavellini Priscila , Levine Andrew J. , Chen Hao , Goya Rodolfo G. , Katcher Harold L.
Published: May 2020

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.
Modeling consensus and distance to delivering indoor residual spray (IRS) implementation strategies to control malaria transmission
Authors: Ryan Sadie , Martin Anne C. , Walia Bhavneet , Winters Anna , Larsen David A
Published: May 2020

Background

Indoor residual spraying (IRS) is an effective method to control malaria-transmittingAnophelesmosquitoes and often complements insecticide-treated mosquito nets, the predominant malaria vector control intervention. With insufficient funds to cover every household, malaria control programs must balance the malaria risk to a particular human community against the financial cost of spraying that community. This study creates a framework for modeling the distance to households for targeting IRS implementation, and applies it to potential risk prioritization strategies in four provinces (Luapula, Muchinga, Eastern, and Northern) in Zambia.

Methods

We used optimal network models to assess the travel distance of routes between operations bases and human communities identified through remote sensing. We compared network travel distances to Euclidean distances, to demonstrate the importance of accounting for road route costs. We then compared the distance to reaching communities for different risk prioritization strategies assuming sufficient funds to spray 50% of households, using four underlying malarial risk maps: a) predictedPlasmodium falciparumparasite rate in 2-10 year olds (PfPR), or b) predicted probability of the presence of each of three main malaria transmitting anopheline vectors (An. arabiensis, An. funestus, An. gambiae)

Results

The estimated one-way network route distance to reach communities to deliver IRS ranged from 0.05 – 115.69 Km. Euclidean distance over and under-estimated these routes by −101.21 – 41.79 Kmper trip, as compared to the network route method. There was little overlap between risk map prioritization strategies, both at a district-by-district scale, and across all four provinces. At both scales, agreement for inclusion or exclusion from IRS across all four prioritization strategies occurred in less than 10% of houses. The distances to reaching prioritized communities were either lower, or not statistically different from non-prioritized communities, at both scales of strategy.

Conclusion

Variation in distance to targeted communities differed depending on risk prioritization strategy used, and higher risk prioritization did not necessarily translate into greater distances in reaching a human community. These findings from Zambia suggest that areas with higher malaria burden may not necessarily be more remote than areas with lower malaria burden.
Typical and atypical language brain organization based on intrinsic connectivity and multitask functional asymmetries
Authors: Labache Loïc , Mazoyer Bernard , Joliot Marc , Crivello Fabrice , Hesling Isabelle , Tzourio-Mazoyer Nathalie
Published: May 2020

Based on the joint investigation in 287 healthy volunteers (150 Left-Handers (LH)) of language task-induced asymmetries and intrinsic connectivity strength of the sentence-processing supramodal network, we show that individuals with atypical rightward language lateralization (N = 30, 25 LH) do not rely on an organization that simply mirrors that of typical leftward lateralized individuals. Actually, the resting-state organization in the atypicals showed that their sentence processing was underpinned by left and right networks both wired for language processing and highly interacting by strong interhemispheric intrinsic connectivity and larger corpus callosum volume. Such a loose hemispheric specialization for language permits the hosting of language in either the left and/or right hemisphere as assessed by a very high incidence of dissociations across various language task-induced asymmetries in this group.
Robust and accurate decoding of hand kinematics from entire spiking activity using deep learning
Authors: Ahmadi Nur , Constandinou Timothy G. , Bouganis Christos-Savvas
Published: May 2020

Robustness and decoding accuracy remain major challenges in the clinical translation of intracortical brain-machine interface (BMI) systems. In this work, we show that a signal/decoder co-design methodology (exploiting the synergism between the input signal and decoding algorithm within the design development process) can be used to yield robust and accurate BMI decoding performance. Specifically, through applying this process, we propose the combination of using entire spiking activity (ESA) as the input signal and quasi-recurrent neural network (QRNN) based deep learning as the decoding algorithm. We evaluated the performance of ESA-driven QRNN decoder for decoding hand kinematics from neural signals chronically recorded from the primary motor cortex area of a non-human primate. Our proposed method yielded consistently higher decoding performance than any other methods previously reported across long-term recording sessions. Its high decoding performance could sustain, even when spikes were removed from the raw signals. Overall results demonstrate exceptionally high decoding accuracy and chronic robustness, which is highly desirable given it is an unresolved challenge in BMIs.
An unexpected lack of difference in superoxide/H2O2production rates in isolated heart and skeletal muscle mitochondria from a mouse model of Barth Syndrome
Authors: Goncalves Renata L. S. , Schlame Michael , Bartelt Alexander , Brand Martin D. , Hotamışlıgil Gökhan S.
Published: May 2020

Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutations in tafazzin and characterized by loss of cardiolipin and severe cardiomyopathy. Mitochondrial superoxide/H2O2production has been implicated in the cardiomyopathy observed in different BTHS models. There are at least 11 mitochondrial sites that produce superoxide/H2O2at significant rates. Which of these sites generate oxidants at excessive rates in BTHS is unknown. Here, we measured the maximum capacity of superoxide/H2O2production from each site in mitochondria isolated from heart and skeletal muscle of the tafazzin knockdown mice (tazkd) at 3, 7 and 12 months of age. Strikingly, the superoxide/H2O2production capacities of these sites were overall indistinguishable between tazkd mice and their wildtype littermates across the time points analyzed. The only exception was site GQin glycerol phosphate dehydrogenase, which was increased in the skeletal muscle of 7 months old tazkd mice. Mitochondrial superoxide/H2O2production was also measuredex vivoduring the oxidation of a complex mixture of substrates mimicking either heart or skeletal muscle cytosol and was found to be indistinguishable between wildtype and tazkd mice. However, we consistently measured decreased FAD-linked respiration in mitochondria isolated from tazkd mice. We conclude that the maximum capacity andex vivorates of superoxide/H2O2production were not increased in mitochondria isolated from heart and skeletal muscle of tazkd mice, despite reduced oxidative capacity. Therefore, it seems unlikely that mitochondrial oxidants contribute to the development of cardiomyopathy in tazkd mice. These observations raise questions about the involvement of mitochondrial oxidants in BTHS pathology.
Oscillatory entrainment mechanisms and anticipatory predictive processes in Autism Spectrum Disorder (ASD)
Authors: Beker Shlomit , Foxe John J. , Molholm Sophie
Published: May 2020

Anticipating near-future events is fundamental to adaptive behavior, whereby neural processing of predictable stimuli is significantly facilitated relative to non-predictable inputs. Neural oscillations appear to be a key anticipatory mechanism by which processing of upcoming stimuli is modified, and they often entrain to rhythmic environmental sequences. Clinical and anecdotal observations have led to the hypothesis that people with Autism Spectrum Disorder (ASD) may have deficits in generating predictions in daily life, and as such, a candidate neural mechanism may be failure to adequately entrain neural activity to repetitive environmental patterns. Here, we tested this hypothesis by interrogating rhythmic entrainment both behaviorally and electrophysiologically. We recorded high-density electroencephalography in children with ASD (n=31) and Typically Developing (TD) age- and IQ-matched controls (n=20), while they reacted to an auditory target as quickly as possible. This auditory event was either preceded by predictive rhythmic visual cues, or not. Results showed that while both groups presented highly comparable evoked responses to the visual stimuli, children with ASD showed reduced neural entrainment to the rhythmic visual cues, and altered anticipation of the occurrence of these stimuli. Further, in both groups, neuro-oscillatory phase coherence correlated with behavior. These results describe neural processes that may underlie impaired event anticipation in children with ASD, and support the notion that their perception of events is driven more by instantaneous sensory inputs and less by their temporal predictability.
A comparison of two methods for estimating measurement repeatability in morphometric studies
Authors: Wylde Zachariah , Bonduriansky Russell
Published: May 2020

Measurement repeatability is often reported in morphometric studies as an index of the contribution of measurement error to trait measurements. However, the common method of remeasuring a mounted specimen fails to capture some components of measurement error, and could therefore yield inflated repeatability estimates. Remounting specimens between successive measurements is likely to provide more realistic estimates of repeatability, particularly for small structures that are difficult to measure.

Using measurements of 22 somatic and genitalic traits of the neriid flyTelostylinus angusticollis, we compared repeatability estimates obtained via remeasuring (where a mounted specimen is measured twice) versus remounting (where a specimen is remounted between measurements). We also asked whether the difference in repeatability estimates obtained via the two methods depends on trait size.

Repeatability estimates obtained via remounting were lower than estimates obtained via remeasuring for each of the 22 traits, and the difference between estimates obtained via the two methods was generally greater for small structures (genitalic traits) than for large structures (legs, wings).

Remounting specimens between successive measurements can provide more accurate estimates of measurement repeatability than remeasuring from a single mount, especially for small structures that are difficult to measure.
Automated design of CRISPR prime editors for thousands of human pathogenic variants
Authors: Morris John A. , Rahman Jahan A. , Guo Xinyi , Sanjana Neville E.
Published: May 2020

Prime editors (PEs) are CRISPR-based genome engineering tools that can introduce precise base-pair edits at specific locations in the genome. These programmable gene editors have been predicted to repair 89% of known human pathogenic variants in the ClinVar database, although these PE constructs do not presently exist. Towards this end, we developed an automated pipeline to correct (therapeutic editing) or introduce (disease modeling) human pathogenic variants that optimizes the design of several RNA constructs required for prime editing and avoids predicted off-targets in the human genome. However, using optimal PE design criteria, we find that only a small fraction of these pathogenic variants can be targeted. Through the use of alternative Cas9 enzymes and extended templates, we increase the number of targetable pathogenic variants to >50,000 variants and make these pre-designed PE constructs accessible through a web-based portal (http://primeedit.nygenome.org). Given the tremendous potential for therapeutic gene editing, we also assessed the possibility of developing universal PE constructs. By examining the overlap of different PE components with common human genetic variants in dbSNP, we find that common variants affect only a small minority of designed PEs.
Flagellar targeting of an arginine kinase requires a conserved lipidated intraflagellar transport (LIFT) pathway inTrypanosoma brucei
Authors: Pandey Maneesha , Huang Yameng , Lim Teck Kwang , Lin Qingsong , He Cynthia Y.
Published: May 2020

Both intraflagellar transport (IFT) and lipidated intraflagellar transport (LIFT) pathways are essential for cilia/flagella biogenesis, motility and sensory functions. In the LIFT pathway, lipidated cargoes are transported into the cilia through the coordinated actions of cargo carrier proteins such as Unc119 or PDE6δ, as well as small GTPases Arl13b and Arl3 in the cilium. Our previous studies revealed a single Arl13b ortholog in the evolutionarily divergentTrypanosoma brucei. TbArl13 catalyses two TbArl3 homologs, TbArl3A and TbArl3C, suggesting the presence of a conserved LIFT pathway in these protozoan parasites. Only a single homolog to the cargo carrier protein Unc119 was identified inT. bruceigenome, but its function in lipidated protein transport has not been characterized. In this study, we exploited the proximity-based biotinylation approach to identify binding partners of TbUnc119. We showed that TbUnc119 binds to a flagellar arginine kinase TbAK3 in a myristoylation-dependent manner and is responsible for its targeting and enrichment in the flagellum. Interestingly, only TbArl3A, but not TbArl3C interacts with TbUnc119 in a GTP-dependant manner, suggesting functional specialization of Arl3-GTPases inT. brucei. This study establishes the function of TbUnc119 as a myristoylated cargo carrier and supports the presence of a conserved LIFT pathway inT. brucei.
Assessing the variation within the oral microbiome of healthy adults
Authors: Nearing Jacob T. , DeClercq Vanessa , Van Limbergen Johan , Langille Morgan G.I.
Published: May 2020

Over 1000 different species of microbes have been found to live within the human oral cavity where they play important roles in maintaining both oral and systemic health. Several studies have identified the core members of this microbial community, however, the factors that determine oral microbiome composition are not well understood. In this study we exam the salivary oral microbiome of 1049 Atlantic Canadians using 16S rRNA gene sequencing in order to determine which dietary, lifestyle, and anthropometric features play a role in shaping microbial community composition. Features that were identified as being significantly associated with overall composition were then additionally examined for genera and amplicon sequence variants that were associated with these features. Several associations were replicated in an additional secondary validation dataset. Overall, we found that several anthropometric measurements including waist hip ratio, height, and fat free mass, as well as age and sex, were associated with oral microbiome composition in both our exploratory and validation cohorts. We were unable to validate dietary impacts on the oral microbiome but did find evidence to suggest potential contributions from factors such as the number of vegetable and refined grain servings an individual consumes. Interestingly, each one of these factors on their own were associated with only minor shifts in the oral microbiome suggesting that future biomarker identification for several diseases associated with the oral microbiome may be undertaken without the worry of confounding factors obscuring biological signal.

Importance

The human oral cavity is inhabited by a diverse community of microbes known as the human oral microbiome. These microbes play a role in maintaining both oral and systemic health and as such have been proposed to be useful biomarkers of disease. However, to identify these biomarkers, we first need to determine the composition and variation of the healthy oral microbiome. Within this report we investigate the oral microbiome of 1049 healthy individuals to determine which genera and amplicon sequence variants are commonly found between individual oral microbiomes. We then further investigate how lifestyle, anthropometric, and dietary choices impact overall microbiome composition. Interestingly, the results from this investigation showed that while many features were significantly associated with oral microbiome composition no single biological factor explained a variation larger than 2%. These results indicate that future work on biomarker detection may be encourage by the lack of strong confounding factors.
Comparative metagenomic analysis following treatment with vancomycin in C57BL/6 and BALB/c mice to elucidate host immunity and behavior
Authors: Ray Pratikshya , Das Debasmita , Pandey Uday , Aich Palok
Published: May 2020

The gut is the largest reservoir of the resident microbiota. The microbiota can affect the host behavior and immunity. While the consequence of treatment with antibiotics on the gut microbiota can be destructive but can be utilized as a tool to understand the host immunity and behavior. The magnitude of perturbation and time needed for the restoration of gut microbiota can depend on the immune bias of the host. In the current study, we therefore, observed the perturbation and restoration kinetics of gut microbiota following treatment with vancomycin and its effect on the host physiology in both Th1-(C57BL/6) and Th2-(BALB/c) biased mice. A comparative metagenomic analysis revealed that the treatment with vancomycin caused a significant decrease in the abundance of Firmicutes and Bacteroidetes phyla and an initial increase in Proteobacteria. Increase in Proteobacteria decreased with continued treatment with vancomycin to result into a significant rise in Verrucomicrobia phylum. We established the patterns of gut microbiota alteration and its effect on a) the behavior of mice, b) expression of key brain molecules and b) immunity related genes. We followed the gut microbiome restoration for a period of two months following withdrawal of treatment with vancomycin. Maximum restoration (>70%) of gut microbiota happened by the 15thday of withdrawal. BALB/c mice showed a more efficient restoration of gut microbiota compared to C57BL/6 mice. The results, in general, revealed that along with the restoration of major gut microbes, important physiological and behavioral changes of both mice strains returned to the normal level.
Detection of SARS-CoV-2 RNA on public surfaces in a densely populated urban
area of Brazil
Authors: Abrahão Jônatas Santos , Sacchetto Lívia , Rezende Izabela Mauricio , Rodrigues Rodrigo , Crispim Ana Paula Correia , Moura César , Mendonça Diogo Correa , Reis Erik , Souza Fernanda , Oliveira Gabriela Fernanda Garcia , Domingos Iago José da Silva , Boratto Paulo , Silva Pedro Henrique Bastos e , Queiroz Victoria Fulgêncio , de Souza Silva Thaís Bárbara , Oliveira Graziele Pereira , de Souza Alves Viviane , Alves Pedro Augusto , Kroon Erna Geessien , de Souza Trindade Giliane , Drumond Betânia Paiva
Published: May 2020

Importance

The COVID-19 pandemic has resulted in more than 3.5 million cases and
245 thousand deaths worldwide as of May 6, 2020. Determining the extent of
the presence of the virus on public surfaces is critical for understanding
the potential risk of infection in these areas.

Objective

To evaluate the presence of SARS-CoV-2 RNA on public surfaces in a
densely populated urban area in Brazil.

Design and Setting

A total of 101 samples were collected from different surfaces in public
places in the region of Belo Horizonte with the highest number of COVID-19
cases. Samples were collected near the hospital and public transportation
areas using sterile swabs, and then submitted to nucleic acid extraction and
genomic detection and quantification by one-step qPCR.

Results

Seventeen of the 101 samples tested positive (16.8%) for SARS-CoV-2 RNA,
including samples from bus stations/terminals, public squares, and
sidewalks, including those near hospitals.

Conclusions and Relevance

Our data indicated the contamination of public surfaces by SARS-CoV-2,
especially near hospital areas, highlighting the risk of infection for the
population. Constant monitoring of the virus in urban areas is required as a
strategy to fight the pandemic and prevent further infections.

Key points

Question

Can SARS-CoV-2 be detected on surfaces in public areas used by a large
proportion of the population?

Findings

SARS-CoV-2 RNA was detected in different locations, including bus
stations/terminals, squares, and sidewalks, especially those near hospitals,
in a densely populated area of Belo Horizonte, Brazil.

Meaning

This study highlights the need for constant monitoring for the presence
of SARS-CoV-2 RNA in urban areas to support better strategies to fight the
COVID-19 pandemic and prevent further infections.
Defensin-driven viral evolution
Authors: Diaz Karina , Hu Ciara T. , Sul Youngmee , Bromme Beth A. , Myers Nicolle D. , Skorohodova Ksenia V. , Gounder Anshu P. , Smith Jason G.
Published: May 2020

Enteric alpha-defensins are potent effectors of innate immunity that are abundantly expressed in the small intestine. Certain enteric bacteria and viruses are resistant to defensins and even appropriate them to enhance infection, despite neutralization of closely related microbes. We therefore hypothesized that defensins impose selective pressure during fecal-oral transmission. Upon passaging a defensin-sensitive serotype of adenovirus in the presence of a human defensin, mutations in the major capsid protein hexon accumulated. In contrast, prior studies identified the vertex proteins as important determinants of defensin antiviral activity. Through infection and biochemical assays, we found that although all major capsid proteins serve a critical role in defensin-mediated neutralization, hexon is the sole determinant of enhancement. These results extensively revise our understanding of the interplay between defensins and non-enveloped viruses. Furthermore, they provide a feasible rationale for defensins shaping viral evolution, resulting in differences in infection phenotypes of closely related viruses.

Author Summary

Defensins are potent antimicrobial peptides that are found on human mucosal surfaces and can directly neutralize viruses. They are abundant in the small intestine, which is constantly challenged by ingested viral pathogens. Interestingly, non-enveloped viruses, such as adenovirus, that infect the gastrointestinal system are unaffected by defensins or can even appropriate defensins to enhance their infection. In contrast, respiratory adenoviruses are neutralized by the same defensins. How enteric viruses overcome defensin neutralization is not well understood. Our studies are the first to show that defensins can drive the evolution of non-enveloped viruses. Furthermore, we identify important components within human adenovirus that dictate sensitivity to defensins. This refined understanding of defensin-virus interactions informs the development of defensin-based therapeutics.
Zika virus infection during pregnancy protects against secondary infection in the absence of CD8+ cells
Authors: Schouest Blake , Gilbert Margaret H. , Bohm Rudolf P , Schiro Faith , Aye Pyone P. , Panganiban Antonito T , Magnani Diogo M. , Maness Nicholas J
Published: May 2020

While T cell immunity is an important component of the immune response to Zika virus (ZIKV) infection generally, the efficacy of these responses during pregnancy remains unknown. Here, we tested the capacity of CD8 lymphocytes to protect from secondary challenge in four macaques, two of which were depleted of CD8+ cells prior to rechallenge with a heterologous ZIKV isolate. The initial challenge during pregnancy produced transcriptional signatures suggesting complex patterns of immune modulation, but all animals efficiently controlled the rechallenge virus, implying that the primary infection conferred adequate protection. The secondary challenge promoted humoral responses and activation of innate and adaptive immune cells, suggesting a brief period of infection prior to clearance. These data confirm that ZIKV infection during pregnancy induces sufficient immunity to protect from a secondary challenge and suggest that this protection is not solely dependent on CD8 T cells but entails multiple arms of the immune system.
Multiple expression assessments of ACE2 and TMPRSS2 SARS-CoV-2 entry molecules in the urinary tract and their associations with clinical manifestations of COVID-19
Authors: Ren Xiaohan , Wei Xiyi , Li Guangyao , Ren Shancheng , Chen Xinglin , Zhang Tongtong , Zhang Xu , Lu Zhongwen , You Zebing , Wang Shangqian , Qin Chao , Song Ninghong , Wang Zengjun
Published: May 2020

Background

Since December 2019, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first spread quickly in Wuhan, China, then globally. From previously published evidence, ACE2 and TMPRSS2, are both pivotal entry molecules that enable cellular infection by SARS-CoV-2. Meanwhile, increased expression of pro-inflammatory cytokines, or a “cytokine storm,” is associated with multiple organ dysfunction syndrome that is often observed in critically ill patients.

Methods

We investigated the expression pattern of ACE2 and TMPRSS2 in major organs in the human body, especially under specific disease conditions. Multiple sequence alignment of ACE2 in different species was used to explain animal susceptibility. Moreover, the cell-specific expression patterns of ACE2 and cytokine receptors in the urinary tract were assessed using single-cell RNA sequencing (scRNA-seq). Additional biological relevance was determined through Gene Set Enrichment Analysis (GSEA) using an ACE2 specific signature.

Results

Our results revealed that ACE2 and TMPRSS2 were highly expressed in genitourinary organs. ACE2 was highly and significantly expressed in the kidney among individuals with chronic kidney diseases or diabetic nephropathy. In single cells, ACE2 was primarily enriched in gametocytes in the testis, and renal proximal tubules. The receptors for pro-inflammatory cytokines, especially IL6ST, were remarkably concentrated in endothelial cells, macrophages, and spermatogonial stem cells in the testis, and renal endothelial cells, which suggested the occurrence of alternative damaging mechanisms via autoimmune attacks.

Conclusions

This study provided new insights into the pathogenicity mechanisms of SARS-CoV-2 that underlie the clinical manifestations observed in the human testis and kidney. These observations might substantially facilitate the development of effective treatments for this rapidly spreading disease.
Photorespiration pathways in a chemolithoautotroph
Authors: Claassens Nico J. , Scarinci Giovanni , Fischer Axel , Flamholz Avi I. , Newell William , Frielingsdorf Stefan , Lenz Oliver , Bar-Even Arren
Published: May 2020

Carbon fixation via the Calvin cycle is constrained by the side activity of Rubisco with dioxygen, generating 2-phosphoglycolate. The metabolic recycling of 2-phosphoglycolate, an essential process termed photorespiration, was extensively studied in photoautotrophic organisms, including plants, algae, and cyanobacteria, but remains uncharacterized in chemolithoautotrophic bacteria. Here, we study photorespiration in the model chemolithoautotrophCupriavidus necator(Ralstonia eutropha) by characterizing the proxy-process of glycolate metabolism, performing comparative transcriptomics of autotrophic growth under low and high CO2concentrations, and testing autotrophic growth phenotypes of gene deletion strains at ambient CO2. We find that the canonical plant-like C2cycle does not operate in this bacterium and instead the bacterial-like glycerate pathway is the main photorespiratory pathway. Upon disruption of the glycerate pathway, we find that an oxidative pathway, which we term the malate cycle, supports photorespiration. In this cycle, glyoxylate is condensed with acetyl-CoA to give malate, which undergoes two oxidative decarboxylation steps to regenerate acetyl-CoA. When both pathways are disrupted, autotrophic growth is abolished at ambient CO2. We present bioinformatic data suggesting that the malate cycle may support photorespiration in diverse chemolithoautotrophic bacteria. This study thus demonstrates a so-far unknown photorespiration pathway, highlighting important diversity in microbial carbon fixation metabolism.
Differential Response of Digesta- and Mucosa-Associated Intestinal Microbiota to Dietary Black Soldier Fly (Hermetia illucens) Larvae Meal in Seawater Phase Atlantic Salmon (Salmo salar)
Authors: Li Yanxian , Bruni Leonardo , Jaramillo-Torres Alexander , Gajardo Karina , Kortner Trond M. , Krogdahl Åshild
Published: May 2020

Intestinal digesta is commonly used for studying responses of microbiota to dietary shifts, yet evidence is accumulating that it represents an incomplete view of the intestinal microbiota. In a 16-week seawater feeding trial, Atlantic salmon (Salmo salar) were fed either a commercially-relevant reference diet or an insect meal diet containing 15% black soldier fly (Hermetia illucens) larvae meal. The digesta- and mucosa-associated distal intestinal microbiota were profiled by 16S rRNA gene sequencing. Regardless of diet, we observed substantial differences between digesta- and mucosa-associated intestinal microbiota. Microbial richness and diversity were much higher in the digesta than the mucosa. The insect meal diet altered the distal intestinal microbiota resulting in higher microbial richness and diversity. The diet effect, however, depended on the sample origin. Digesta-associated intestinal microbiota showed more pronounced changes than the mucosa-associated microbiota. Lastly, multivariate association analyses identified two mucosa-enriched taxa,Brevinema andersoniiand unclassifiedSpirochaetaceae, associated with the expression of genes related to immune responses and barrier function in the distal intestine, respectively. Overall, our data clearly indicate that responses in digesta- and mucosa-associated microbiota to dietary inclusion of insect meal differ, with the latter being more resilient to dietary changes.
A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability
Authors: Chi Xiangyang , Yan Renhong , Zhang Jun , Zhang Guanying , Zhang Yuanyuan , Hao Meng , Zhang Zhe , Fan Pengfei , Dong Yunzhu , Yang Yilong , Chen Zhengshan , Guo Yingying , Zhang Jinlong , Li Yaning , Song Xiaohong , Chen Yi , Xia Lu , Fu Ling , Hou Lihua , Xu Junjie , Yu Changming , Li Jianmin , Zhou Qiang , Chen Wei
Published: May 2020

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.