bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain activation and connectivity in anorexia nervosa and body dysmorphic disorder when viewing bodies: relationships to clinical symptoms and perception of appearance
Authors: Moody Teena D , Morfini Francesca , Cheng Gigi , Sheen Courtney L , Kerr Wesley , Strober Michael , Feusner Jamie D
Published: February 2020

Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are characterized by distorted perception of appearance, yet no studies have directly compared the neurobiology associated with body perception. We compared brain activation and connectivity in relevant networks when viewing images of others’ bodies and tested their relationships with clinical symptoms and subjective appearance evaluations. We acquired fMRI data from 64 unmedicated females (20 weight-restored AN, 23 BDD, 21 controls) during a matching task using photos of others’ bodies that were unaltered or spatial-frequency filtered. With general linear model and independent components analyses we compared brain activation and connectivity in visual, striatal, and parietal networks and performed univariate and partial least squares multivariate analyses to investigate relationships with clinical symptoms and appearance evaluations. BDD but not AN demonstrated hypoactivity in dorsal visual and parietal networks compared to controls. Yet, AN and BDD showed partially overlapping patterns of hyperconnectivity in the dorsal visual network and hypoconnectivity in parietal network compared with controls. Further, there were significant activity and connectivity differences between AN and BDD in both networks. In both groups, activity and/or connectivity were associated with symptom severity and appearance ratings of others’ bodies. AN and BDD demonstrate both distinct and partially overlapping aberrant neural phenotypes involved in body processing and visually encoding global features. Nevertheless, in each disorder, aberrant activity and connectivity show relationships to clinically relevant symptoms and subjective perception. Results have implications for understanding distinct and shared pathophysiology underlying perceptual distortions for appearance and may inform future novel treatment strategies.
Integrative kinomics reveals kinase-driven subtypes of gastric adenocarcinomas with sunitinib as a potential common inhibitor
Authors: Tapken Maria Johanna , Haag Georg Martin , Jäger Dirk , Fröhling Stefan , Mock Andreas
Published: February 2020

Molecular subtyping of tumors promises a personalized stratification into different treatment regimens. In gastric adenocarcinoma, the four molecularly defined subtypeschromosomal instable (CIN), microsatellite unstable (MSI), genomically stable (GS)andEBV-positivesubtype have been proposed. Following an integrative kinomics approach this computational analysis aimed to predict the best kinase inhibitor for every molecular subtype of gastric adenocarcinomas using publicly available TCGA data (n=404). Intriguingly, using the regulatory network of gastric cancer to estimate protein activity, 43% of all samples could be identified to be kinase-driven. These samples were divided into three clusters with mutually exclusive kinase activities that were independent of the established molecular subtypes. Integrating the pattern of kinase overexpression with an unsupervised target landscape of 37 approved clinical kinase drugs revealed that sunitinib had the best target spectrum across the activated kinases in all three sample clusters. Future work is warranted to validate the kinase-driven subsets of gastric cancer and sunitinib as a potential common inhibitor.
MicroExonator enables systematic discovery and quantification of microexons across mouse embryonic development
Authors: Parada Guillermo E. , Munita Roberto , Georgakopoulos-Soares Ilias , Fernandez Hugo , Metzakopian Emmanouil , Andres Maria Estela , Miska Eric A. , Hemberg Martin
Published: February 2020

Microexons, exons that are ≤30 nucleotides, were shown to play key roles in neuronal development, but are difficult to detect and quantify using standard RNA-Seq alignment tools. Here, we present MicroExonator, a novel pipeline for reproduciblede novodiscovery and quantification of microexons. We processed 289 RNA-seq datasets from eighteen mouse tissues corresponding to nine embryonic and postnatal stages, providing the most comprehensive survey of microexons available for mouse. We detected 2,984 microexons, 332 of which are differentially spliced throughout mouse embryonic brain development, including 29 that are not present in mouse transcript annotation databases. Unsupervised clustering of microexons alone segregates brain tissues by developmental time and further analysis suggest a key function for microexon inclusion in axon growth and synapse formation. Finally, we analysed single-cell RNA-seq data from the mouse visual cortex and we report differential inclusion between neuronal subpopulations, suggesting that some microexons could be cell-type specific.
phyloregion: R package for biogeographic regionalization and spatial conservation
Authors: Daru Barnabas H. , Karunarathne Piyal , Schliep Klaus
Published: February 2020

Biogeographical regionalization is the classification of regions in terms of their biotas and is key to understanding biodiversity patterns across the world. Previously, it was only possible to perform analysis of biogeographic regionalization on small datasets, often using tools that are difficult to replicate.

Here, we presentphyloregion, a package for the analysis of biogeographic regionalization and spatial conservation in the R computing environment, tailored for mega phylogenies and macroecological datasets of ever-increasing size and complexity.

Compared to available packages,phyloregionis three to four orders of magnitude faster and memory efficient for cluster analysis, determining optimal number of clusters, evolutionary distinctiveness of regions, as well as analysis of more standard conservation measures of phylogenetic diversity, phylogenetic endemism, and evolutionary distinctiveness and global endangerment.

A case study of zoogeographic regionalization for 9574 species of squamate reptiles (amphisbaenians, lizards, and snakes) across the globe, reveals their evolutionary affinities, using visualization tools that allow rapid identification of patterns and underlying processes with user-friendly colours–for example– indicating the levels of differentiation of the taxa in different regions.

Ultimately,phyloregionwould facilitate rapid biogeographic analyses that accommodates the ongoing mass-production of species occurrence records and phylogenetic datasets at any scale and for any taxonomic group into completely reproducible R workflows.
Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12
Authors: Chen Zhuoyao , Wasney Gregory A. , Picaud Sarah , Filippakopoulos Panagis , Vedadi Masoud , D’Angiolella Vincenzo , Bullock Alex N.
Published: February 2020

Wnt signaling is critically dependent on dishevelled proteins (DVL1-3), which are required to assemble an intracellular Wnt signalosome at the plasma membrane. The levels of dishevelled proteins are strictly regulated by multiple E3 ubiquitin ligases that target DVL1-3 for ubiquitination and proteasomal degradation. The BTB-Kelch family protein KLHL12 is a substrate-specific adaptor for a Cullin-RING E3 ligase complex that contains Cullin3 and Rbx1. KLHL12 was the first E3 ligase to be identified for DVL1-3, but the molecular mechanisms determining its substrate interactions have remained unknown. Here, we mapped the interaction of DVL1-3 to a ‘PGXPP’ motif that is conserved in other known partners and substrates of KLHL12, including PLEXHA4, PEF1 and SEC31. A 20-mer peptide containing the DVL1 motif bound to the Kelch domain of KLHL12 with low micromolar affinity. In cells, the mutation or deletion of this motif caused a striking reduction in the binding, ubiquitination and stability of DVL1 confirming this sequence as a degron motif for KLHL12 recruitment. To determine the binding mechanism we solved a 2.4 Å crystal structure of the Kelch domain of KLHL12 in complex with a DVL1 peptide. The structure revealed that the DVL1 substrate adopted a U-shaped turn conformation that enabled hydrophobic interactions with all six blades of the Kelch domain β-propeller. Overall, these results define the molecular mechanisms determining DVL regulation by KLHL12 and establish the KLHL12 Kelch domain as a new protein interaction module for a novel proline-rich motif.
Dynamic Vision Training Transfers Positively to Batting Performance Among Collegiate Baseball Batters
Authors: Liu Sicong , Ferris Lyndsey M. , Hilbig Susan , Asamoa Edem , LaRue John L. , Lyon Don , Connolly Katie , Port Nicholas , Appelbaum L. Gregory
Published: February 2020

A growing body of evidence demonstrates visual, perceptual, and oculomotor abilities contribute to batting performance in baseball and there is interest in whether training such abilities can transfer positively to batting performance. The current study tested this question through a pre-registered randomized, and placebo-controlled intervention, conducted with 24 collegiate baseball players at two Division 1 universities. Athletes were randomized to receive either dynamic vision training consisting of stroboscopic, anticipatory timing, and eye quickness drills, or placebo drills stylized after control procedures in previous vision therapy studies. Generalized near-transfer was tested via a digital visual-motor task battery (n= 20), while sports-specific intermediate and far transfer of training were evaluated through instrumented batting practice metrics (n= 14) and box score performance in NCAA-sanctioned games (n= 12). The effects of training group were tested on these outcome measures while controlling for covariates such as pre-training expectations and site. Participants averaged 8.50 hours of training with no significant training group differences in adherence, expectations, or baseline assessments. ANCOVA revealed no group differences in measures of visual-motor skills or NCAA game statistics. However, batting practice demonstrated significant improvements in launch angle (p= 0.002, Cohen’sd= 0.74) and hit distance (p< 0.001, Cohen’sd= 0.70) for the active cohort relative to the placebo control. This controlled and pre-registered pilot study therefore provides preliminary evidence that vision training may improve batting practice performance, creating new opportunities for the transfer of skill training and warranting further study.

Pre-Registration

At Open Science Framework on August 9, 2018. DOI 10.17605/OSF.IO/496RX. Accessible athttps://osf.io/jxh8u
Long-term repeatability in social behaviours suggests stable social phenotypes in wild chimpanzees
Authors: Tkaczynski Patrick J. , Mielke Alexander , Samuni Liran , Preis Anna , Wittig Roman , Crockford Catherine
Published: February 2020

Animals living in social groups navigate challenges when competing and cooperating with other group members. Changes in demographics, dominance hierarchies or ecological factors, such as food availability or disease prevalence, are expected to influence decision-making processes regarding social interactions. Therefore, it could be expected individuals show flexibility in social behaviour over time to maximise the fitness benefits of social living. To date, research across species has shown that stable inter-individual differences in social behaviour exist, but mostly over relatively short data collection time periods. Using data spanning over 20 years, we demonstrate that multiple social behaviours are repeatable over the long-term in wild chimpanzees, a long-lived species occupying a complex fission-fusion society. We controlled for temporal, ecological and demographic changes, limiting pseudo-repeatability. We conclude that chimpanzees living in natural ecological settings have relatively stable long-term social phenotypes over years that may be independent of life history stage or strategies. Our results add to the growing body of literature suggesting consistent individual differences in social tendencies are more likely the rule rather than the exception in group-living animals.
Enhancing CRISPR deletion via pharmacological delay of DNA-PK
Authors: Bosch Núria , Medová Michaela , Esposito Roberta , Pulido-Quetglas Carlos , Zimmer Yitzhak , Johnson Rory
Published: February 2020

CRISPR-Cas9 deletion (CRISPR-del) is the leading approach for eliminating DNA from mammalian cells and underpins a variety of genome-editing applications. Target DNA, defined by a pair of double strand breaks (DSBs), is removed during non-homologous end-joining (NHEJ). However, the low efficiency of CRISPR-del results in laborious experiments and false negative results. Using an endogenous reporter system, we demonstrate that temporary inhibition of DNA-dependent protein kinase (DNA-PK) – an early step in NHEJ - yields up to 17-fold increase in DNA deletion. This is observed across diverse cell lines, gene delivery methods, commercial inhibitors and guide RNAs, including those that otherwise display negligible activity. Importantly, the method is compatible with pooled functional screens employing lentivirally-delivered guide RNAs. Thus, delaying the kinetics of NHEJ relative to DSB formation is a simple and effective means of enhancing CRISPR-deletion.
Sensory- and memory-related drivers for altered ventriloquism effects and aftereffects in older adults
Authors: Park Hame , Nannt Julia , Kayser Christoph
Published: February 2020

The manner in which humans exploit multisensory information for subsequent decisions changes with age. Multiple causes for such age-effects are being discussed, including a reduced precision in peripheral sensory representations, changes in cognitive inference about causal relations between sensory cues, and a decline in memory contributing to altered sequential patterns of multisensory behaviour. To dissociate these putative contributions, we investigated how healthy young and older adults integrate audio-visual spatial information within trials (the ventriloquism effect) and between trials (the ventriloquism aftereffect). With both a model-free and (Bayesian) model-based analyses we found that both biases differed between groups. Our results attribute the age-change in the ventriloquism bias to a decline in spatial hearing rather than a change in cognitive processes. This decline in peripheral function, combined with a more prominent influence from preceding responses rather than preceding stimuli in the elderly, can also explain the observed age-effect in the ventriloquism aftereffect. Our results suggest a transition from a sensory- to a behavior-driven influence of past multisensory experience on perceptual decisions with age, due to reduced sensory precision and change in memory capacity.
Mitochondrial respiration is required to provide amino acids during fermentative proliferation of fission yeast
Authors: Malecki Michal , Kamrad Stephan , Ralser Markus , Bähler Jürg
Published: February 2020

When glucose is available, many organisms repress mitochondrial respiration in favour of aerobic glycolysis, or fermentation in yeast, that suffices for ATP production. Fission yeast cells, however, rely partially on respiration for rapid proliferation under fermentative conditions. Here we determined the limiting factors that require respiratory function during fermentation. When the electron transport chain was inhibited, supplementation with arginine was necessary and sufficient to restore rapid cell proliferation. Accordingly, a systematic screen for mutants growing poorly without arginine identified not only mutants defective in arginine synthesis but also mutants defective in mitochondrial oxidative metabolism. Genetic or pharmacological inhibition of respiration triggered a drop in intracellular levels of arginine and amino acids derived from the Krebs-cycle metabolite alpha-ketoglutarate: glutamine, lysine and glutamic acid. Conversion of arginine into these amino acids was required for rapid proliferation when the respiratory chain was blocked. The respiratory block triggered an immediate gene-expression response diagnostic of TOR inhibition, which was muted by arginine supplementation or without the AMPK-activating kinase Ssp1. The TOR-controlled proteins featured biased composition of amino acids reflecting their shortage after respiratory inhibition. We conclude that respiration supports rapid proliferation in fermenting cells of fission yeast by boosting the supply of Krebs-cycle derived amino acids.
Self-assembly based post-translational protein oscillators
Authors: Kimchi Ofer , Goodrich Carl P. , Courbet Alexis , Curatolo Agnese I. , Woodall Nicholas B. , Baker David , Brenner Michael P.
Published: February 2020

Recent advances in synthetic post-translational protein circuits are significantly impacting the landscape of biomimicry engineering. However, designing sustained dynamic phenomena in these circuits remains an outstanding challenge. Inspired by the KaiABC system regulating the circadian clock in cyanobacteria, we develop two experimentally realizable post-translational oscillators. The oscillators rely on a small number of components interacting only through reversible binding and phosphorylation/dephosphorylation reactions.
Cryptic diversity in the model fern genusCeratopteris(Pteridaceae)
Authors: Kinosian Sylvia P. , Pearse William D. , Wolf Paul G.
Published: February 2020

Cryptic species are present throughout the tree of life. They are especially prevalent in ferns, because of processes such hybridization, polyploidy, and reticulate evolution. In addition, the morphological simple body plan of ferns limits phenotypic variation and makes it difficult to detect crypic species in ferns without molecular work. The model fern genusCeratopterishas long been suspected to harbor cryptic diversity, specifically in the highly polymorphicC. thalictroides. Yet no studies have included samples from throughout the pan-tropical range ofCeratopterisor utilized genomic sequencing, making it difficult to assess the full extent of cryptic variation within this genus. Here, we present the first multilocus phylogeny of the genus using reduced representation genomic sequencing (RADseq) and examine population structure, phylogenetic relationships, and ploidy level variation. We recover similar species relationships found in previous studies, find support for a named cryptic species as genetically distinct, and identify a novel putative species from withinC. thalictroides sensu latuin Central and South America.
The estrogenic pathway modulates non-breeding female aggression in a teleost fish
Authors: Zubizarreta Lucía , Silva Ana C. , Quintana Laura
Published: February 2020

Aggressive behaviors are widespread among animals and are critical in the competition for resources. The physiological mechanisms underlying aggression have mostly been examined in breeding males, in which gonadal androgens, acting in part through their aromatization to estrogens, have a key role. There are two alternative models that contribute to further understanding hormonal mechanisms underlying aggression: aggression displayed in the non-breeding season, when gonadal steroids are low, and female aggression. In this study we approach, for the first time, the modulatory role of estrogens and androgens upon non-breeding aggression in a wild female teleost fish. We characterized female aggression in the weakly electric fishGymnotus omarorumand carried out acute treatments 1 h prior to agonistic encounters with either an aromatase inhibitor or an antagonist of androgen receptors. Aromatase inhibition caused a strong distortion of aggressive behavior whereas anti-androgen treatment had no effect on behavior. Territorial non-breeding aggression in femaleG. omarorumis robust and depended on rapid estrogen actions to maintain high levels of aggression, and ultimately reach conflict resolution from which dominant/subordinate status emerged. Our results taken together with our own reports in males and the contributions from non-breeding aggression in bird and mammal models, suggest a conserved strategy involving fast-acting estrogens in the control of this behavior across species. In addition, further analysis of female non-breeding aggression may shed light on potential sexual differences in the fine tuning of social behaviors.

Highlights

FemaleGymnotus omarorumdisplayed robust territorial aggression in lab settings.

Acute treatment with aromatase inhibitor lowered aggression levels.

Aromatase inhibition increased first attack latency and decreased conflict resolution.

Acute treatment with anti-androgens showed no effects.

This is the first report of estrogens underlying teleost non-breeding female aggression.
How young is your Muscle? A Machine Learning framework for motor functional assessment with ageing by NMF based analysis of HD-sEMG signal
Authors: Banerjee Swati , Boudaoud Sofiane , Kinugawa-Burron Kiyoka
Published: February 2020

Objective

With ageing, there are various changes in the autonomic nervous system and a simultaneous decline in the motor functional abilities of the human body. This study falls within the framework improvement of the clinical tools dedicated to the robust evaluation of motor function efficiency with ageing.

Method

Analysis of HD-sEMG signals recorded from 32 channels during Sit To Stand (STS) test are used for the functional assessment of body muscles. For this purpose, five primary characteristic features,iEMG, ARV, RMS, Skewness, Kurtosis, are employed for the study. A channel clustering approach is proposed based on the parameters using Non Negative Matrix Factorization (NMF).

Results

The NMF based clustering of the HD-sEMG channels seems to be sensitive toward modifications of the muscle activation strategy with ageing during STS test.

Conclusion

This manuscript provides a framework for the assessment of Motor Functional Age(MFA) of subjects having a range of chronological from 25 yrs to 75 yrs. The groups were made a decade apart and it was found that the MFA varies with the level of activeness of the muscle under study and a premature ageing is observed according to the change in activation pattern of the HD-sEMG grid.
Ecological theory applied to environmental metabolomes reveals compositional divergence despite conserved molecular properties
Authors: Danczak Robert E. , Goldman Amy E. , Chu Rosalie K. , Toyoda Jason G. , Garayburu-Caruso Vanessa A. , Tolić Nikola , Graham Emily B. , Morad Joseph W. , Renteria Lupita , Wells Jacqueline R. , Herzog Skuyler P. , Ward Adam S. , Stegen James C.
Published: February 2020

Stream and river systems transport and process substantial amounts of dissolved organic matter (DOM) from terrestrial and aquatic sources to the ocean, with global biogeochemical implications. However, the underlying mechanisms affecting the spatiotemporal organization of DOM composition are under-investigated. To understand the principles governing DOM composition, we leverage the recently proposed synthesis of metacommunity ecology and metabolomics, termed ‘meta-metabolome ecology.’ Applying this novel approach to a freshwater ecosystem, we demonstrated that despite similar molecular properties across metabolomes, metabolite identity significantly diverged due to environmental filtering. We refer to this phenomenon as ‘thermodynamic redundancy,’ which is analogous to the ecological concept of functional redundancy. We suggest that under thermodynamic redundancy, divergent metabolomes can support equivalent biogeochemical function just as divergent ecological communities can support equivalent ecosystem function. As these analyses are performed in additional ecosystems, potentially generalizable principles, like thermodynamic redundancy, can be revealed and provide insight into DOM dynamics.
No detectable alloreactive transcriptional responses during donor-multiplexed single-cell RNA sequencing of peripheral blood mononuclear cells
Authors: McGinnis Christopher S. , Siegel David A. , Xie Guorui , Stone Mars , Gartner Zev J. , Roan Nadia R. , Lee Sulggi A.
Published: February 2020

Single-cell RNA sequencing (scRNA-seq) provides high-dimensional measurement of transcript counts in individual cells. However, high assay costs limit the study of large numbers of samples. Sample multiplexing technologies such as antibody hashing and MULTI-seq use sample-specific sequence tags to enable individual samples (e.g., different patients) to be sequenced in a pooled format before downstream computational demultiplexing. Critically, no study to date has evaluated whether the mixing of samples from different donors in this manner results in significant changes in gene expression resulting from alloreactivity (i.e., response to non-self immune antigens). The ability to demonstrate minimal to no alloreactivity is crucial to avoid confounded data analyses, particularly for cross-sectional studies evaluating changes in immunologic gene signatures,. Here, we compared the expression profiles of peripheral blood mononuclear cells (PBMCs) from a single donor with and without pooling with PBMCs isolated from other donors with different blood types. We find that there was no evidence of alloreactivity in the multiplexed samples following three distinct multiplexing workflows (antibody hashing, MULTI-seq, andin silicogenotyping using souporcell). Moreover, we identified biases amongst antibody hashing sample classification results in this particular experimental system, as well as gene expression signatures linked to PBMC preparation method (e.g., Ficoll-Paque density gradient centrifugation with or without apheresis using Trima filtration).
Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants
Authors: Hicks Allison L. , Kissler Stephen M. , Mortimer Tatum D. , Ma Kevin C. , Taiaroa George , Ashcroft Melinda , Williamson Deborah A. , Lipsitch Marc , Grad Yonatan H.
Published: February 2020

Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate and ineffective antibiotic use. However, because such assays infer resistance phenotypes based on the presence or absence of known genetic markers, their utility will wane in response to the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance designed to ensure early detection of novel resistance variants, but efficient strategies to do so remain to be defined. Here, we evaluate the efficiency of targeted sampling approaches informed by patient and pathogen characteristics in detecting genetic variants associated with antibiotic resistance or diagnostic escape inNeisseria gonorrhoeae, focusing on this pathogen because of its high burden of disease, the imminent threat of treatment resistance, and the use and ongoing development of genotype-based diagnostics. We show that incorporating patient characteristics, such as demographics, geographic regions, or anatomical sites of isolate collection, into sampling approaches is not a reliable strategy for increasing variant detection efficiency. In contrast, sampling approaches informed by pathogen characteristics, such as genomic diversity and genomic background, are significantly more efficient than random sampling in identifying genetic variants associated with antibiotic resistance and diagnostic escape.
Metagenomic insights into the metabolism and ecologic functions of the widespread DPANN archaea from deep-sea hydrothermal vents
Authors: Cai Ruining , Zhang Jing , Liu Rui , Sun Chaomin
Published: February 2020

Due to the particularity of metabolism and the importance of ecological roles, the archaea living in deep-sea hydrothermal system always attract great attention. Included, the DPANN superphylum archaea, which are massive radiation of organisms, distribute widely in hydrothermal environment, but their metabolism and ecology remain largely unknown. In this study, we assembled 20 DPANN genomes comprised in 43 reconstructed genomes from deep-sea hydrothermal sediments, presenting high abundance in the archaea kingdom. Phylogenetic analysis shows 6 phyla comprising Aenigmarchaeota, Diapherotrites, Nanoarchaeota, Pacearchaeota, Woesearchaeota and a new candidate phylum designated DPANN-HV-2 are included in the 20 DPANN archaeal members, indicating their wide diversity in this extreme environment. Metabolic analysis presents their metabolic deficiencies because of their reduced genome size, such as gluconeogenesis,de novonucleotide and amino acid synthesis. However, they possess alternative and economical strategies to fill this gap. Furthermore, they were detected to have multiple capacities of assimilating carbon dioxide, nitrogen and sulfur compounds, suggesting their potentially important ecologic roles in the hydrothermal system.

IMPORTANCE

DPANN archaea show high distribution in the hydrothermal system. However, they possess small genome size and some incomplete biological process. Exploring their metabolism is helpful to know how such small lives adapt to this special environment and what ecological roles they play. It was ever rarely noticed and reported. Therefore, in this study, we provide some genomic information about that and find their various abilities and potential ecological roles. Understanding their lifestyles is helpful for further cultivating, exploring deep-sea dark matters and revealing microbial biogeochemical cycles in this extreme environment.
Quantifying bias of COVID-19 prevalence and severity estimates in Wuhan, China that depend on reported cases in international travelers
Authors: Niehus Rene , De Salazar Pablo M. , Taylor Aimee R. , Lipsitch Marc
Published: February 2020

Risk of COVID-19 infection in Wuhan has been estimated using imported case counts of international travelers, often under the assumption that all cases in travelers are ascertained. Recent work indicates variation among countries in detection capacity for imported cases. Singapore has historically had very strong epidemiological surveillance and contact-tracing capacity and has shown in the COVID-19 epidemic evidence of a high sensitivity of case detection. We therefore used a Bayesian modeling approach to estimate the relative imported case detection capacity for other countries compared to that of Singapore.We estimate that the global ability to detect imported cases is 38% (95% HPDI 22% - 64%) of Singapore’s capacity. Equivalently, an estimate of 2.8 (95% HPDI 1.5 - 4.4) times the current number of imported cases, could have been detected, if all countries had had the same detection capacity as Singapore. Using the second component of the Global Health Security index to stratify likely case-detection capacities, we found that the ability to detect imported cases relative to Singapore among high surveillance locations is 40% (95% HPDI 22% - 67%), among intermediate surveillance locations it is 37% (95% HPDI 18% - 68%), and among low surveillance locations it is 11% (95% HPDI 0% - 42%). Using a simple mathematical model, we further find that treating all travelers as if they were residents (rather than accounting for the brief stay of some of these travelers in Wuhan) can modestly contribute to underestimation of prevalence as well. We conclude that estimates of case counts in Wuhan based on assumptions of perfect detection in travelers may be underestimated by several fold, and severity correspondingly overestimated by several fold. Undetected cases are likely in countries around the world, with greater risk in countries of low detection capacity and high connectivity to the epicenter of the outbreak.
Concurrent of stunting and overweight/obesity among children: evidence from Ethiopia
Authors: Farah Alinoor Mohamed , Nour Tahir Yousuf , Endris Bilal Shikur , Gebreyesus Seifu Hagos
Published: February 2020

Background

Nutrition transition in many low- and middle-income countries (LMICs) has led to childhood nutritional outcomes to shift from a predominance of undernutrition to a dual burden of under- and overnutrition. Yet, Infant and young child feeding programs in Ethiopia mainly focus on undernutrition. It is therefore crucial to assess the prevalence and determinants to better inform infant young child feeding programs.

Methods

We analyzed anthropometric, sociodemographic and dietary data of children aged 6-23 months from 2016 Ethiopian Demographic and Health Survey (EDHS). A total of 2,674 children were included in the current study. Concurrent of Stunting and Overweight/Obesity (CSO) prevalence was estimated by distal, intermediate and proximal factors. To identify factors associated with CSO, we conducted hierarchical logistic regression analyses.

Results

The overall prevalence of CSO was 2.45%. The odds of CSO was significantly higher in children of low household wealth category, compared to their counter parts in the richest category (AOR=2.07, 95%CI=1.06–4.03, P=0.033). In boys, the likelihood of CSO was 1.60 times that of girls (95%CI =1.03–2.49, P=0.038). Above 12months of age was significantly associated with a higher odd of CSO, compared to below 12months of age (AOR=1.76, 95% CI=1.07– 2.88, P=0.026).

Small birth size was significantly associated with a higher odd of CSO, compared to large birth size (AOR=2.53, 95%CI=1.45–4.41, P=0.001). Children who did not take vitamin A supplement within the previous six months had a higher odd of CSO, compared to those who took (AOR=1.91, 95%CI =1.19–3.07, P =0.007).

Conclusion

Our study provided evidence on the co-existence of stunting and overweight/obesity among infants and young children in Ethiopia. CSO was associated with various factors originating from community and child levels. Therefore, identifying children at risk of growth flattering and excess weight gain provides IYCF programs in Ethiopia and beyond with an opportunity of earlier interventions.
Causal dynamical modelling predicts novel regulatory genes of FOXP3 in human regulatory T cells
Authors: Sawlekar Rucha , Magni Stefano , Capelle Christophe , Baron Alexandre , Zeng Ni , Mombaerts Laurent , Yue Zuogong , Yuan Ye , He Feng Q. , Gonçalves Jorge
Published: February 2020

Regulatory T cells (Tregs), characterized as a CD4+CD25+FOXP3+ subset of T cells, are vital to the induction of immune tolerance and the maintenance of immune homeostasis. While target genes of Treg master regulator FOXP3 have been identified, the upstream regulatory machinery of FOXP3 still remains largely unknown. Here we dynamically modelcausalrelationships among genes from available time-series genome-scale datasets, to predict direct or indirect regulatory genes of FOXP3 in human primary Tregs. From the whole genome, we selected five top ranked candidates for further experimental validation. Following knockdown, three out of the five candidates indeed showed significant effects on the mRNA expression of FOXP3. Further experiments showed that one out of these three predicted candidates, namely nuclear receptor binding factor 2 (NRBF2), also affected FOXP3 protein expression. These results open new doors to identify potential new mechanisms of immune related diseases.
Alteration of Power Law Scaling of Spontaneous Brain Activity in Schizophrenia
Authors: Lee Yi-Ju , Huang Su-Yun , Lin Ching-Po , Tsai Shih-Jen , Yang Albert C.
Published: February 2020

Nonlinear dynamical analysis has been used to quantify the complexity of brain signal at temporal scales. Power law scaling is a well-validated method in physics that has been used to describe the complex nature of a system across different time scales. In this research, we investigated the change of power-law characteristics in a large-scale resting-state fMRI data of schizophrenia (N = 200) and healthy participants (N = 200) derived from Taiwan Aging and Mental Illness cohort. Fourier transform was used to determine the power spectral density (PSD) of resting-state fMRI signal. We estimated the power law scaling of PSD of resting-state fMRI signal by determining the slope of the regression line fitting to the log-log plot of PSD. The power law scaling represents the dynamical properties of resting-state fMRI signal ranging from noisy oscillation (e.g., white noise) to complex fluctuations (e.g., slope approaches −1). Linear regression model was used to assess the statistical difference in power law scaling between schizophrenia and healthy participants. The significant differences in power law scaling were found in six brain regions. Schizophrenia patients has significantly more positive power law scaling (i.e., frequency components become more homogenous) at four brain regions: left precuneus, left medial dorsal nucleus, right inferior frontal gyrus, and right middle temporal gyrus, compared with healthy participants. Additionally, schizophrenia exhibited less positive power law scaling (i.e., frequency components are more dominant at lower frequency range) in bilateral putamen. Significant correlations of power law scaling with the severity of psychosis were found in these identified brain areas in schizophrenia. These findings suggest that schizophrenia has abnormal brain signal complexity toward random patterns, which is linked to psychotic symptoms. The power law scaling analysis may serve as a novel functional brain imaging marker for evaluating patients with mental illness.
Poor availability of context-specific evidence hampers decision-making in conservation
Authors: Christie Alec P. , Amano Tatsuya , Martin Philip A. , Petrovan Silviu O. , Shackelford Gorm E. , Simmons Benno I. , Smith Rebecca K. , Williams David R. , Wordley Claire F. R. , Sutherland William J.
Published: February 2020

Evidence-based conservation relies on robust and relevant evidence. Practitioners often prefer locally relevant studies whose results are more likely to be transferable to the context of planned conservation interventions. To quantify the availability of relevant evidence for amphibian and bird conservation we reviewed Conservation Evidence, a database of quantitative tests of conservation interventions. Studies were geographically clustered and found at extremely low densities - fewer than one study was present within a 2,000 km radius of a given location. The availability of relevant evidence was extremely low when we restricted studies to those studying biomes or taxonomic orders containing high percentages of threatened species, compared to the most frequently studied biomes and taxonomic orders. Further constraining the evidence by study design showed that only 17-20% of amphibian and bird studies used robust designs. Our results highlight the paucity of evidence on the effectiveness of conservation interventions, and the disparity in evidence for local contexts that are frequently studied and those where conservation needs are greatest. Addressing the serious global shortfall in context-specific evidence requires a step change in the frequency of testing conservation interventions, greater use of robust study designs and standardized metrics, and methodological advances to analyze patchy evidence bases.
Integrative analyses to investigate the link between microbial activity and metabolites degradation during anaerobic digestion
Authors: Cardona Laetitia , Lê Cao Kim Anh , Puig-Castellví Francesc , Bureau Chrystelle , Madigou Céline , Mazéas Laurent , Chapleur Olivier
Published: February 2020

Anaerobic digestion (AD) is a promising biological process which converts waste into sustainable energy. To fully exploit AD’s capability, we need to deepen our knowledge of the microbiota involved in this complex bioprocess. High-throughput methodologies open new perspectives to investigate AD process at the molecular level, supported by recent data integration methodologies to extract relevant information. In this study, we investigated the link between microbial activity and substrate degradation in a lab-scale anaerobic co-digestion experiment, where bioreactors were fed with 9 different mixtures of three co-substrates (fish waste, sewage sludge, and grass). Samples were profiled using 16S rRNA sequencing and untargeted metabolomics. In this article, we propose a suite of multivariate tools to statistically integrate these data and identify coordinated patterns between groups of microbial and metabolic profiles specific of each co-substrate. Five main groups of features were successfully evidenced, including cadaverine degradation found to be associated with the activity of microorganisms from the orderClostridialesand the genusMethanosarcina. This study highlights the potential of data integration towards a comprehensive understanding of AD microbiota.
Live cell imaging reveals that RecA finds homologous DNA by reduced dimensionality search
Authors: Wiktor Jakub , Gynnå Arvid H , Leroy Prune , Larsson Jimmy , Coceano Giovanna , Testa Ilaria , Elf Johan
Published: February 2020

Homologous recombination (HR) is essential for the accurate repair of double-stranded DNA breaks (DSBs); it begins when the RecBCD2 complex resects the ends of the DSB into 3' single-stranded DNA (ssDNA) on which a RecA filament assembles. HR depends on the ability of this RecA-ssDNA filament to locate the homologous repair template on the sister chromosome. The mechanism by which the homology is located among vast amounts of heterologous DNA is not yet understood, despite a long history of research. Here, we directly visualize the repair of DSBs in hundreds of individual cells, using high-throughput microfluidics and fluorescence microscopy. We find that in E. coli, DSB repair is completed in 15 minutes without fitness loss. We further show that the search takes less than 10 minutes and is mediated by a thin, highly dynamic RecA filament that stretches throughout the cell. We propose a model in which the architecture of the RecA filament effectively reduces search dimensionality to two dimensions. The model is corroborated by the observation that the search time does not depend on the length of the cell or the amount of DNA, and also predicts a search time that is consistent with our measurement. Since the RecA family proteins are conserved in all organisms, our results also translate to other systems that rely on homologous recombination.
Efficient Immune Cell Genome Engineering with Improved CRISPR Editing Tools
Authors: Chan Waipan , Gottschalk Rachel A. , Yao Yikun , Pomerantz Joel L. , Germain Ronald N.
Published: February 2020

CRISPR (clustered regularly interspaced short palindromic repeats)-based methods have revolutionized genome engineering and the study of gene-phenotype relationships. However, modifying cells of the innate immune system, especially macrophages, has been challenging because of cell pathology and low targeting efficiency resulting from nucleic acid activation of sensitive intracellular sensors. Likewise, lymphocytes of the adaptive immune system are largely refractory to CRISPR-enhanced homology-directed repair (HDR) due to inefficient or toxic delivery of donor templates via transient transfection methods. To overcome these challenges and limitations, we developed three improved methods for CRISPR-based genome editing using a hit-and-run transient expression strategy to minimize off-target effects and generate more precise genome editing. Overall, our enhanced CRISPR tools and strategies designed to tackle both murine and human immune cell genome engineering are expected to be widely applicable not only in hematopoietic cells but also other mammalian cell types of interest.

All animal experiments were done in accordance with the guidelines of the NIAID/NIH Institutional Animal Care and Use Committee.
Reversal of β-amyloid induced microglial toxicityin vitroby activation of Fpr2/3
Authors: Wickstead Edward S. , Karim Husnain A. , Manuel Roberta E. , Biggs Christopher , Getting Stephen J. , McArthur Simon
Published: February 2020

Background and Purpose

Microglial inflammatory activity is thought to be a major contributor to the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD), and strategies to restrain their behaviour are under active investigation. Classically, anti-inflammatory approaches aim to suppress pro-inflammatory mediator production, but exploitation of inflammatory resolution, the endogenous process whereby an inflammatory reaction is terminated, has not been fully investigated as a therapeutic approach in AD. In this study, we sought to provide proof-of-principal that the major pro-resolving actor, formyl peptide receptor 2, Fpr2, could be targeted to reverse microglial activation induced by the AD-associated pro-inflammatory stimulus, oligomeric β-amyloid (oAβ).

Experimental Approach

The immortalised murine microglial cell line BV2 was employed as a model system to investigate the pro-resolving effects of the Fpr2 ligand QC1 upon oAβ-induced inflammatory, oxidative and metabolic behaviour. Cytotoxic behaviour of BV2 cells was assessed through use of co-cultures with retinoic acid-differentiated human SH-SY5Y cells.

Key Results

Stimulation of BV2 cells with oAβ at 100nM did not induce classical inflammatory marker production but did stimulate production of reactive oxygen species (ROS), an effect that could be reversed by subsequent treatment with the Fpr2 ligand QC1. Further investigation revealed that oAβ-induced ROS production was associated with NADPH oxidase activation and a shift in BV2 cell metabolic phenotype, activating the pentose phosphate pathway and NADPH production, changes that were again reversed by QC1 treatment. Microglial oAβ-stimulated ROS production was sufficient to induce apoptosis of bystander SH-SY5Y cells, an effect that could be prevented by QC1 treatment.

Conclusion and Implications

In this study, we provide proof-of-concept data that indicate exploitation of the pro-resolving receptor Fpr2 can reverse damaging oAβ-induced microglial activation. Future strategies aiming to restrain neuroinflammation in conditions such as AD should examine pro-resolving actors as a mechanism to harness the brain’s endogenous healing pathways and limit neuroinflammatory damage.
Slightly beneficial genes are retained by evolving Horizontal Gene Transfer despite selfish elements
Authors: van Dijk B. , Hogeweg P. , Doekes H.M. , Takeuchi N.
Published: February 2020

Horizontal gene transfer (HGT) is a key component of bacterial evolution, which in concert with gene loss can result in rapid changes in gene content. While HGT can evidently aid bacteria to adapt to new environments, it also carries risks since bacteria may pick up selfish genetic elements (SGEs). Here, we use modeling to study how bacterial growth rates are affected by HGT of slightly beneficial genes, if bacteria can evolve HGT to improve their growth rates, and when HGT is evolutionarily maintained in light of harmful SGEs. We find that we can distinguish between four classes of slightly beneficial genes: indispensable, enrichable, rescuable, and unrescuable genes. Rescuable genes – genes that confer small fitness benefits and are lost from the population in the absence of HGT — can be collectively retained by a bacterial community that engages in HGT. While this ‘gene-sharing’ cannot evolve in well-mixed cultures, it does evolve in a spatially structured population such as a biofilm. Although HGT does indeed enable infection by harmful SGEs, HGT is nevertheless evolutionarily maintained by the hosts, explaining the stable coexistence and co-evolution of bacteria and SGEs.