bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression profiles of circRNAs, lncRNAs, and mRNAs in extreme phenotypes of diabetic retinopathy
Authors: Zhou Rouxi , Liu Sen , Wang Wei , Cheng Weijing , He Miao , Xiong Kun , Gong Xia , Li Yuting , Huang Wenyong
Published: February 2020

Recent evidences highlighted regulatory role of circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) in the development of diabetic retinopathy (DR). However, the literatures and number of the RNAs identified were limited. Here, we compared the expression profiles of circRNAs, lncRNAs, and mRNAs in the blood of the susceptible individuals who developed severe DR within 5 years after being diagnosed with type 2 diabetic mellitus (T2DM), and the inherently resistant individuals who are spared from DR despite over 20-year history of T2DM. Using RNA microarray, hundreds of significantly differently expressed circRNAs, lncRNAs, and dozens of mRNAs were identified. Quantitative polymerase chain reaction verified the above findings. Gene ontology analysis indicated that the differentially expressed circRNAs were involved in platelet-derived growth factor binding, and mRNA and the cis-target genes of lncRNA participate in negative regulation of the Wnt signaling pathway. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that the differentially expressed circRNAs were related to vitamin B6 metabolism and type 2 diabetes. The cis-target genes of lncRNAs are enriched in valine, leucine, and isoleucine biosynthesis and in the hypoxia-inducible factor-1 signaling pathway. The trans-target genes of lncRNAs are enriched in pathways such as vitamin B6 metabolism. Differentially expressed mRNAs are associated with type 2 diabetes and the vascular endothelial growth factor signaling pathway. Our findings demonstrate that circRNAs and lncRNAs may be involved in the regulation of DR and lay a foundation for further researches into the underlying mechanisms.
Fractal kinetics of COVID-19 pandemic (with update 3/1/20)
Authors: Ziff Anna L. , Ziff Robert M.
Published: February 2020

We give an update to the original paper posted on 2/17/20 – now (as of 3/1/20) the China deaths are rapidly decreasing, and we find an exponential decline to the power law similar to the that predicted by the network model of Vazquez [2006]. At the same time, we see non-China deaths increasing rapidly, and similar to the early behavior of the China statistics. Thus, we see three stages of the spread of the disease in terms of number of deaths: exponential growth, power-law behavior, and then exponential decline in the daily rate.

(Original abstract) The novel coronavirus (COVID-19) continues to grow rapidly in China and is spreading in other parts of the world. The classic epidemiological approach in studying this growth is to quantify a reproduction number and infection time, and this is the approach followed by many studies on the epidemiology of this disease. However, this assumption leads to exponential growth, and while the growth rate is high, it is not following exponential behavior. One approach that is being used is to simply keep adjusting the reproduction number to match the dynamics. Other approaches use rate equations such as the SEIR and logistical models. Here we show that the current growth closely follows power-law kinetics, indicative of an underlying fractal or small-world network of connections between susceptible and infected individuals. Positive deviations from this growth law might indicate either a failure of the current containment efforts while negative deviations might indicate the beginnings of the end of the pandemic. We cannot predict the ultimate extent of the pandemic but can get an estimate of the growth of the disease.
Estimating the case fatality ratio of the COVID-19 epidemic in China
Authors: Wang Xing , Ma Zihui , Ning Yi , Chen Chen , Chen Rujin , Chen Qiwen , Zhang Heng , Li Chunming , He Yan , Wang Tao , Tong Cheng , Wu Junqing , Li Yuyan , Ma Handong , Zhang Shaodian , Zhao Hongxin
Published: February 2020

Background

Corona Virus Disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan city and rapidly spread throughout China since late December 2019. Crude case fatality ratio (CFR) with dividing the number of known deaths by the number of confirmed cases does not represent the true CFR and might be off by orders of magnitude. We aim to provide a precise estimate of the CFR of COVID-19 using statistical models at the early stage of the epidemic.

Methods

We extracted data from the daily released epidemic report published by the National Health Commission P. R. China from 20 Jan 2020, to 1 March 2020. Competing risk model was used to obtain the cumulative hazards for death, cure, and cure-death hazard ratio. Then the CFR was estimated based on the slope of the last piece in joinpoint regression model, which reflected the most recent trend of the epidemic.

Results

As of 1 March 2020, totally 80,369 cases were diagnosed as COVID-19 in China. The CFR of COVID-19 were estimated to be 70.9% (95% CI: 66.8%-75.6%) during Jan 20-Feb 2, 20.2% (18.6%-22.1%) during Feb 3-14, 6.9% (6.4%-7.4%) during Feb 15-23, 1.5% (1.4%-1.6%) during Feb 24-March 1 in Hubei province, and 20.3% (17.0%-25.3%) during Jan 20-28, 1.9% (1.8%-2.1%) during Jan 29-Feb 12, 0.9% (0.8%-1.1%) during Feb 13-18, 0.4% (0.4%-0.5%) during Feb 19-March 1 in other areas of China, respectively.

Conclusions

Based on analyses of public data, we found that the CFR in Hubei was much higher than that of other regions in China, over 3 times in all estimation. The CFR would follow a downwards trend based on our estimation from recently released data. Nevertheless, at early stage of outbreak, CFR estimates should be viewed cautiously because of limited data source on true onset and recovery time.
Leading causes of mortality and prescription drug coverage in Canada and New Zealand
Authors: Rawson Nigel S B
Published: February 2020

Background

Canada may soon see the introduction of a national pharmaceutical insurance system. New Zealand has a government-funded healthcare system used by all residents that operates within a tight cost-containment budget.

Objective

To compare the main mortality causes in Canada and New Zealand and examine listings in current Canadian provincial public drug plans and the New Zealand national drug formulary.

Methods

Age-standardized mortality rates from 1985 to 2014 and data on hospital discharges and average length of stay in hospital for Canada and New Zealand were obtained from the Organization for Economic Cooperation and Development’s website. Information on insured medications was obtained from Canadian provincial drug plan lists and the New Zealand Pharmaceutical Schedule current in mid-2019.

Results

Mortality rates for acute myocardial infarction, ischemic heart disease and cerebrovascular disease were higher, on average over the 30-year observation period, in New Zealand, but rates for malignancies and respiratory disorders were similar in the two countries. Reimbursement listing rates for drugs for cancer and some cardiovascular indications were lower in New Zealand than in Canada.

Conclusions

New Zealand’s drug coverage system has contained costs, but it restricts or denies access to new innovative medicines with the potential to improve patients’ lives. Although a New Zealand-style national pharmacare scheme in Canada would offer the opportunity to restrain drug expenditure, it would likely fail to satisfy patients and healthcare providers and diminish health outcomes, resulting in higher costs in other healthcare sectors.
Modulation of metabolic functions through Cas13d-mediated gene knockdown in liver
Authors: He Bingbing , Peng Wenbo , Huang Jia , Zhang Hang , Zhou Yingsi , Yang Xiali , Liu Jing , Li Zhijie , Xu Chunlong , Xue Mingxing , Yang Hui , Huang Pengyu
Published: February 2020

RNA knockdownin vivocarries significant potential for disease modelings and therapies. Despite the emerging approaches of CRISPR/Cas9-mediated permanent knock out of targeted genes, strategies targeting RNA for disruption are advantageous in the treatment of acquired metabolic disorders when permanent modification of the genome DNA is not appropriate, and RNA virus infection diseases when pathogenic DNA is not available (such as SARS-Cov-2 and MERS infections). Recently, Cas13d, a family of RNA-targeting CRISPR effectors, has been shown to accomplish robust down-regulation of cellular RNAs in mammalian cellsin vitro. Among the various Cas13d subtypes, CasRx (RfxCas13d) showed the most potent RNA knockdown efficiency in HEK293T cells. However, the RNA-targeting activity of Cas13d still needs to be verifiedin vivo. In this study, the CasRx system was demonstrated to efficiently and functionally knock down genes related to metabolism functions, includingPten, Pcsk9andlncLstr, in mouse hepatocytes. CasRx-mediated simultaneous knockdown of multiple genes was also achieved by sgRNA arrays, providing a useful strategy to modulate complex metabolism networks. Moreover, the AAV (adeno-associated virus)-mediated delivery ofCasRxandPcsk9sgRNAs into mouse liver successfully decreased serum PCSK9, resulting in significant reduction of serum cholesterol levels. Importantly, CasRx-mediated knockdown ofPcsk9is reversible andPcsk9could be repeatedly down-regulated, providing an effective strategy to reversibly modulate metabolic genes. The present work supplies a successful proof-of-concept trial that suggests efficient and regulatory knockdown of target metabolic genes for a designed metabolism modulation in the liver.
Isolation and Characterization of 2019-nCoV-like Coronavirus from Malayan Pangolins
Authors: Xiao Kangpeng , Zhai Junqiong , Feng Yaoyu , Zhou Niu , Zhang Xu , Zou Jie-Jian , Li Na , Guo Yaqiong , Li Xiaobing , Shen Xuejuan , Zhang Zhipeng , Shu Fanfan , Huang Wanyi , Li Yu , Zhang Ziding , Chen Rui-Ai , Wu Ya-Jiang , Peng Shi-Ming , Huang Mian , Xie Wei-Jun , Cai Qin-Hui , Hou Fang-Hui , Liu Yahong , Chen Wu , Xiao Lihua , Shen Yongyi
Published: February 2020

The outbreak of 2019-nCoV in the central Chinese city of Wuhan at the end of 2019 poses unprecedent public health challenges to both China and the rest world1. The new coronavirus shares high sequence identity to SARS-CoV and a newly identified bat coronavirus2. While bats may be the reservoir host for various coronaviruses, whether 2019-nCoV has other hosts is still ambiguous. In this study, one coronavirus isolated from Malayan pangolins showed 100%, 98.2%, 96.7% and 90.4% amino acid identity with 2019-nCoV in the E, M, N and S genes, respectively. In particular, the receptor-binding domain of the S protein of the Pangolin-CoV is virtually identical to that of 2019-nCoV, with one amino acid difference. Comparison of available genomes suggests 2019-nCoV might have originated from the recombination of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like virus. Infected pangolins showed clinical signs and histopathological changes, and the circulating antibodies reacted with the S protein of 2019-nCoV. The isolation of a coronavirus that is highly related to 2019-nCoV in the pangolins suggests that these animals have the potential to act as the intermediate host of 2019-nCoV. The newly identified coronavirus in the most-trafficked mammal could represent a continuous threat to public health if wildlife trade is not effectively controlled.
Integrative omics approach to identify the molecular architecture of inflammatory protein levels in healthy older adults
Authors: Hillary Robert F. , Trejo-Banos Daniel , Kousathanas Athanasios , McCartney Daniel L. , Harris Sarah E. , Stevenson Anna J. , Patxot Marion , Ojavee Sven Erik , Zhang Qian , Liewald David C. , Ritchie Craig W. , Evans Kathryn L. , Tucker-Drob Elliot M. , Wray Naomi R. , McRae Allan F. , Visscher Peter M. , Deary Ian J. , Robinson Matthew R. , Marioni Riccardo E.
Published: February 2020

The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets. Therefore, in this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink®inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches). We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified three CpG sites spread across three proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to one polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease, and between IL12B and Crohn’s disease. Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.
Hand-reared wolves show attachment comparable to dogs and use human caregiver as a social buffer in the Strange Situation Test
Authors: Wheat Christina Hansen , Larsson Linn , Berner Patricia , Temrin Hans
Published: February 2020

Domesticated animals are generally assumed to display increased sociability towards humans compared to their wild ancestors. Dogs (Canis familiaris) have a remarkable ability to form social relationships with humans, including lasting attachment, a social bond based on emotional dependency. Since it has specifically been suggested that the ability to form attachment with humans evolved post-domestication in dogs, attempts to quantify attachment in wolves (Canis lupus), the ancestor of dogs, have subsequently been performed. However, while these rare wolf studies do highlight the potential for wolves to express attachment behaviour towards humans, the varied, and in some cases, contrasting results also emphasize the need for further testing of wolves. Here we used the standardized Strange Situation Test to investigate attachment behaviour expressed in wolves and dogs hand-reared and socialized under identical conditions. We found that 23 weeks old wolves and dogs equally discriminated between a stranger and a familiar person, and expressed similar attachment behaviours toward a familiar person. Additionally, wolves, but not dogs, expressed significantly elevated stress behaviour during the test, but this stress response was buffered by the presence of a familiar person. Wolves also expressed quantifiable fear responses to the stranger, whereas no such response was detectable in dogs. Together, our results suggest that wolves can show attachment toward humans comparable to that of dogs. Importantly, our findings demonstrate that the ability to form attachment with humans exists in relatives of the wild ancestor of dogs, thus refuting claims that such attachment is unique to post-domestication dog lineages.
Functional Ensemble Survival Tree: Dynamic Prediction of Alzheimer’s Disease Progression Accommodating Multiple Time-Varying Covariates
Authors: Jiang By Shu , Xie Yijun , Colditz Graham A.
Published: February 2020

With the exponential growth in data collection, multiple time-varying biomarkers are commonly encountered in clinical studies, along with rich set of baseline covariates. This paper is motivated by addressing a critical issue in the field of Alzheimer’s disease (AD) in which we aim to predict the time for AD conversion in people with mild cognitive impairment to inform prevention and early treatment decisions. Conventional joint models of biomarker trajectory with time-to-event data rely heavily on model assumptions and may not be applicable when the number of covariates is large. This thus motivated us to consider a functional ensemble survival tree framework to characterize the joint effects of both functional and baseline covariates in predicting disease progression. The proposed framework incorporates multivariate functional principal component analysis to characterize the changing patterns of multiple time-varying neurocognitive biomarker trajectories and then nest these features within an ensemble survival tree in predicting the progression of AD. We provide a fast implementation of the algorithm that accommodates personalized dynamic prediction that can be updated as new observations are gathered to reflect the patient’s latest prognosis. The algorithm is empirically shown to perform well in simulation studies and is illustrated through the analysis of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We provide implementation of our proposed method inRpackagefunest.
Mutation bias can shape adaptation in large asexual populations experiencing clonal interference
Authors: Gomez Kevin , Bertram Jason , Masel Joanna
Published: February 2020

The Extended Evolutionary Synthesis invokes a role for development in shaping adaptive evolution, which in population genetics terms corresponds to mutation-biased adaptation. Critics have claimed that clonal interference makes mutation-biased adaptation rare. We consider the behavior of two simultaneously adapting traits, one with larger mutation rateU, the other with larger selection coefficients, using asexual traveling wave models. We find that adaptation is dominated by whichever trait has the faster rate of adaptationvin isolation, with the other trait subject to evolutionary stalling. Reviewing empirical claims for mutation-biased adaptation, we find that not all occur in the “origin-fixation” regime of population genetics wherevis only twice as sensitive tosas toU. In some cases, differences inUare at least ten to twelve times larger than differences ins, as needed to cause mutation-biased adaptation even in the “multiple mutations” regime. Surprisingly, whenU>sin the “diffusive-mutation” regime, the required sensitivity ratio is also only two, despite pervasive clonal interference. Given two traits with identicalv, the benefit of having highersis surprisingly small, occurring largely when one trait is at the boundary between the origin-fixation and multiple mutations regimes.
Identification of Characteristic Genomic Markers in Human Hepatoma Huh7 and Huh7.5.1-8 Cell Lines
Authors: Kawamoto Masaki , Yamaji Toshiyuki , Saito Kyoko , Satomura Kazuhiro , Endo Toshinori , Fukasawa Masayoshi , Hanada Kentaro , Osada Naoki
Published: February 2020

The human hepatoma-derived Huh7 cell line and its derivatives (Huh7.5 and Huh7.5.1) have been widely used as a convenient experimental substitute for primary hepatocytes. In particular, these cell lines represent host cells suitable for propagating the hepatitis C virus (HCV)in vitro. The Huh7.5.1-8 cell line, a subline of Huh7.5.1, can propagate HCV more efficiently than its parental cells. To provide genomic information for cells’ quality control, we performed whole-genome sequencing of Huh7 and Huh7.5.1-8 and identified their characteristic genomic deletions, some of which are applicable to an in-house test for cell authentication. Among the genes related to HCV infection and replication, 53 genes were found to carry missense or loss-of-function mutations likely specific to the Huh7 and/or Huh7.5.1-8. Eight genes, includingDDX58(RIG-I),BAX, EP300, andSPP1(osteopontin), contained mutations observed only in Huh7.5.1-8 or mutations with higher frequency in Huh7.5.1-8. These mutations might be relevant to phenotypic differences between the two cell lines and may also serve as genetic markers to distinguish Huh7.5.1-8 cells from the ancestral Huh7 cells.
IHS: an integrative method for the identification of network hubs
Authors: Salavaty Abbas , Ramialison Mirana , Currie Peter D
Published: February 2020

Biological systems are composed of highly complex networks and decoding the functional significance of individual network components is critical for understanding healthy and diseased states. Several algorithms have been designed to identify the most influential regulatory points, or hub nodes, within a network. However, none of the current methods correct for inherent positional biases which limits their applicability. In addition, none of the currently available hub detection algorithms effectively combine network centrality measures together. To overcome this computational deficit, we undertook a statistical assessment of 200 real-world and simulated networks to decipher associations between centrality measures, and developed a novel algorithm termed “integrated hubness score” (IHS), which integrates the most important and commonly used network centrality measures, namely degree centrality, betweenness centrality and neighbourhood connectivity, in an unbiased way. When compared against the four most commonly used hub identification methods on four independent validated biological networks, the IHS algorithm outperformed all other assessed methods. Using this novel and universal method, researchers of any discipline can now identify the most influential network nodes.
Flexible annotation atlas of the mouse brain: combining and dividing brain structures of the Allen Brain Atlas while maintaining anatomical hierarchy
Authors: Takata Norio , Sato Nobuhiko , Komaki Yuji , Okano Hideyuki , Tanaka Kenji F.
Published: February 2020

A brain atlas is necessary for analyzing structure and function in neuroimaging research. Although various annotation volumes (AVs) for the mouse brain have been proposed, it is common in magnetic resonance imaging (MRI) of the mouse brain that regions-of-interest (ROIs) for brain structures (nodes) are created arbitrarily according to each researcher’s necessity, leading to inconsistent ROIs among studies. One reason for such a situation is the fact that earlier AVs were fixed,i.e.combination and division of nodes were not implemented. This report presents a pipeline for constructing a flexible annotation atlas (FAA) of the mouse brain by leveraging public resources of the Allen Institute for Brain Science on brain structure, gene expression, and axonal projection. A mere two-step procedure with user-specified, text-based information and Python codes constructs FAA with nodes which can be combined or divided objectively while maintaining anatomical hierarchy of brain structures. Four FAAs with total node count of 4, 101, 866, and 1,381 were demonstrated. Unique characteristics of FAA realized analysis of resting-state functional connectivity (FC)acrossthe anatomical hierarchy andamongcortical layers, which were thin but large brain structures. FAA can improve the consistency of whole brain ROI definition among laboratories by fulfilling various requests from researchers with its flexibility and reproducibility.

Highlights

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A flexible annotation atlas (FAA) for the mouse brain is proposed.

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FAA is expected to improve whole brain ROI-definition consistency among laboratories.

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The ROI can be combined or divided objectively while maintaining anatomical hierarchy.

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FAA realizes functional connectivity analysisacrossthe anatomical hierarchy.

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Codes for FAA reconstruction is available athttps://github.com/ntakata/flexible-annotation-atlas

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Datasets for resting-state fMRI in awake mice are available athttps://openneuro.org/datasets/ds002551
Effective containment explains sub-exponential growth in confirmed cases of recent COVID-19 outbreak in Mainland China
Authors: Maier Benjamin F. , Brockmann Dirk
Published: February 2020

The recent outbreak of COVID-19 in Mainland China is characterized by a distinctive algebraic, sub-exponential increase of confirmed cases with time during the early phase of the epidemic, contrasting an initial exponential growth expected for an unconstrained outbreak with sufficiently large reproduction rate. Although case counts vary significantly between affected provinces in Mainland China, the scaling law tμ is surprisingly universal, with a range of exponents μ = 2.1 ± 0.3. The universality of this behavior indicates that, in spite of social, regional, demographical, geographical, and socio-economical heterogeneities of affected Chinese provinces, this outbreak is dominated by fundamental mechanisms that are not captured by standard epidemiological models. We show that the observed scaling law is a direct consequence of containment policies that effectively deplete the susceptible population. To this end we introduce a parsimonious model that captures both, quarantine of symptomatic infected individuals as well as population wide isolation in response to mitigation policies or behavioral changes. For a wide range of parameters, the model reproduces the observed scaling law in confirmed cases and explains the observed exponents. Quantitative fits to empirical data permit the identification of peak times in the number of asymptomatic or oligo-symptomatic, unidentified infected individuals, as well as estimates of local variations in the basic reproduction number. The model implies that the observed scaling law in confirmed cases is a direct signature of effective contaiment strategies and/or systematic behavioral changes that affect a substantial fraction of the susceptible population. These insights may aid the implementation of containment strategies in potential export induced COVID-19 secondary outbreaks elsewhere or similar future outbreaks of other emergent infectious diseases.
Estimating maximal oxygen consumption from heart rate response to submaximal ramped treadmill test
Authors: Gonzales Tomas I. , Westgate Kate , Hollidge Stefanie , Lindsay Tim , Jeon Justin , Brage Søren
Published: February 2020

The Cambridge Ramped Treadmill Test (CRTT) is an incremental, multistage exercise test (I: steady-state walk, II: walk ramped speed, III: walk ramped incline, and IV: run ramped speed on flat). It is typically deployed as a submaximal test with flexible test termination criteria, making it an attractive option for population-based studies of cardiorespiratory fitness. We conducted a study in healthy adults to test the validity of maximal oxygen consumption estimates (VO2 max; ml O2·kg-1·min-1) predicted from CRTT heart rate response using several methods: a heart rate-to-work rate linear regression method across several test termination criteria, either when a percentage of age-predicted maximal heart rate was achieved (50% through 100%) or at the end of distinct CRTT stages (II, III, and IV); and two single-point walk-test calibration methods using data from either CRTT stage I (low-point method) or stage II (high-point method). For estimates from the linear regression method, prediction bias ranged from −3.0 to −1.6 ml O2·kg-1·min-1 and Pearson’s r ranged from 0.57 to 0.79 for endpoints at percentages of age-predicted maximal heart rate; results were similar for stages III and IV endpoints, but predictions using data only up to stage II had poorer agreement. Agreement was moderate when using the low-point (mean bias: −4.3 ml O2·kg-1·min-1; Pearson’s r: 0.71) and high-point (mean bias: −3.5 ml O2·kg-1·min-1; Pearson’s r: 0.69) methods. Heart rate response to the CRTT can be used to predict VO2max with acceptable validity in common epidemiological scenarios.
Is migraine associated to brain anatomical alterations? New data and coordinate-based meta-analysis
Authors: Masson Rémy , Demarquay Geneviève , Meunier David , Lévêque Yohana , Hannoun Salem , Bidet-Caulet Aurélie , Caclin Anne
Published: February 2020

A growing number of studies investigate brain anatomy in migraine using voxel-(VBM) and surface-based morphometry (SBM), as well as diffusion tensor imaging (DTI). The purpose of this article is to identify consistent patterns of anatomical alterations associated with migraine. First, 19 migraineurs without aura and 19 healthy participants were included in a brain imaging study. T1-weighted MRIs and DTI sequences were acquired and analyzed using VBM, SBM and tract-based spatial statistics. No significant alterations of gray matter (GM) volume, cortical thickness, cortical gyrification, sulcus depth and white-matter tract integrity could be observed. However, migraineurs displayed decreased white matter (WM) volume in the left superior longitudinal fasciculus. Second, a systematic review of the literature employing VBM, SBM and DTI was conducted to investigate brain anatomy in migraine. Meta-analysis was performed using Seed-based d Mapping via permutation of subject images (SDM-PSI) on GM volume, WM volume and cortical thickness data. Alterations of GM volume, WM volume, cortical thickness or white-matter tract integrity were reported in 72%, 50%, 56% and 33% of published studies respectively. Spatial distribution and direction of the disclosed effects were highly inconsistent across studies. The SDM-PSI analysis revealed neither significant decrease nor significant increase of GM volume, WM volume or cortical thickness in migraine. Overall there is to this day no strong evidence of specific brain anatomical alterations reliably associated to migraine. Possible explanations of this conflicting literature are discussed.

Trial registration number

NCT02791997, registrated February 6th, 2015.
Leveraging prior concept learning improves ability to generalize from few examples in computational models of human object recognition
Authors: Rule Joshua S. , Riesenhuber Maximilian
Published: February 2020

Humans quickly learn new visual concepts from sparse data, sometimes just a single example. Decades of prior work have established the hierarchical organization of the ventral visual stream as key to this ability. Computational work has shown that networks which hierarchically pool afferents across scales and positions can achieve human-like object recognition performance and predict human neural activity. Prior computational work has also reused previously acquired features to efficiently learn novel recognition tasks. These approaches, however, require magnitudes of order more examples than human learners and only reuse intermediate features at the object level or below. None has attempted to reuse extremely high-level visual features capturing entire visual concepts. We used a benchmark deep learning model of object recognition to show that leveraging prior learning at the concept level leads to vastly improved abilities to learn from few examples. These results suggest computational techniques for learning even more efficiently as well as neuroscientific experiments to better understand how the brain learns from sparse data. Most importantly, however, the model architecture provides a biologically plausible way to learn new visual concepts from a small number of examples, and makes several novel predictions regarding the neural bases of concept representations in the brain.

Author summary

We are motivated by the observation that people regularly learn new visual concepts from as little as one or two examples, far better than, e.g., current machine vision architectures. To understand the human visual system’s superior visual concept learning abilities, we used an approach inspired by computational models of object recognition which: 1) use deep neural networks to achieve human-like performance and predict human brain activity; and 2) reuse previous learning to efficiently master new visual concepts. These models, however, require many times more examples than human learners and, critically, reuse only low-level and intermediate information. None has attempted to reuse extremely high-level visual features (i.e., entire visual concepts). We used a neural network model of object recognition to show that reusing concept-level features leads to vastly improved abilities to learn from few examples. Our findings suggest techniques for future software models that could learn even more efficiently, as well as neuroscience experiments to better understand how people learn so quickly. Most importantly, however, our model provides a biologically plausible way to learn new visual concepts from a small number of examples.
The intriguing dynamics of chromatin folding and assembly
Authors: Yang Z. , Miao W. , Mofrad M. R.K.
Published: February 2020

We investigate the dynamics of chromatin folding based on the “strings and binders” (SBS) model with molecular dynamics simulation. SBS model is a coarse-grained model considering a self-avoiding chain interacting with diffusive binders. By introducing transition among different categories of beads with specific transition cycles and transition probabilities, our model is capable of introducing different dynamics quantitatively during the folding process, thus capturing variety of phenomena related to chromatin dynamics. Firstly, roles of dynamics in the process of chromatin folding were examined. We discovered that there is a minimum gyration of chromatin under varying characteristic times of transition which indicates neither dramatically dynamic nor static folding process is optimal for chromatin to reach stable states with relatively low free energy. Secondly, it is noticeable that when beads transit from or into others in distinct dynamics, the equilibrium concentrations are distinct as well. As a consequence, the distribution of chromatin loop length is relevant to the dynamics of binders which can be modified by complex such as Wings apart-like protein homolog (Wapl) and SCC2/SCC4 cohesin loader complex (SCC2/SCC4). Finally, our model is able to reproduce contact matrices of both wild type HAP1 cell and ΔWAPL HAP1 cell obtained from Hi-C technology with a relatively high accuracy. Our model recapitulate the accumulating contacts at the corners of TADs and vanishing short-range contacts along the diagonal, manifesting the difference of chromatin structures before and after eliminating WAPL.

STATEMENT OF SIGNIFICANCE

Our model includes reciprocal transition among beads in SBS model to introduce different dynamics in chromatin folding process. Our model is able to examine the roles of dynamics in chromatin folding, reveal the loop length variation due to the concentration imbalance caused by distinct dynamics and reproduce contact matrices of both wild type and WAPL-deficient cells. Our research work provides a model to investigate the dynamics of chromatin folding quantitatively and displays its significance of revealing multiple experimental results using computational tools.
Floating frogs sound larger: environmental constraints on signal production drives call frequency changes
Authors: Goutte Sandra , Muñoz Matías I. , Ryan Michael J. , Halfwerk Wouter
Published: February 2020

In animal communication, receivers benefit from signals providing reliable information on signallers’ traits of interest. Individuals involved in conflicts, such as competition between rivals, should pay particular attention to cues that are ‘unfakeable’ by the senders due to the intrinsic properties of the production process. In bioacoustics, the best-known example of such ‘index signals’ is the relationship between a sender’s body size and the dominant frequency of their vocalizations. Dominant frequency may however not only depend on an animal’s morphology but also on the interaction between the sound production system and its immediate environment. Here, we experimentally altered the environment surrounding calling frogs and assessed its impact on the signal produced. More specifically, we altered water level, which forced frogs to float on the surface and tested how this manipulation affected the shuttling of air between the lungs and the vocal sac, and how this in turn impacted the calls’ dominant frequency. Our results show that frogs that are floating are able to fully inflate their lungs and vocal sacs, and that the associated change in airflow or air pressure is correlated with a decrease of call dominant frequency.
Yaphaploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy
Authors: Masson Christel , García-García Diana , Bitard Juliette , Grellier Élodie-Kim , Roger Jérôme E. , Perron Muriel
Published: February 2020

Hippo signalling regulates eye growth during embryogenesis through its effectors YAP and TAZ. Taking advantage of aYapheterozygous mouse line, we here sought to examine its function in adult neural retina, where YAP expression is restricted to Müller glia. We first discovered an unexpected temporal dynamic of gene compensation. At post-natal stages,Tazupregulation occurs, leading to a gain of function-like phenotype characterized by EGFR signalling potentiation and delayed cell cycle exit of retinal progenitors. In contrast,Yap+/-adult retinas no longer exhibit TAZ-dependent dosage compensation. In this context,Yaphaploinsufficiency in aged individuals results in Müller glia dysfunction, late-onset cone degeneration and reduced cone-mediated visual response. Alteration of glial homeostasis and altered patterns of cone opsins were also observed in Müller cell specific conditionalYapknockout mice. Together, this study highlights a novel YAP function in Müller cells for the maintenance of retinal tissue homeostasis and the preservation of cone integrity. It also suggests that YAP haploinsufficiency should be considered and explored as a cause of cone dystrophies in human.

Main Points

This study finds unsuspected dynamics of YAP compensatory mechanisms in the retina ofYap+/-mice

Yaphaploinsufficiency results in Müller glia dysfunction in aged mice, leading to late-onset cone dystrophy
Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differential modulation of ABC transporters on chronic myeloid leukemias
Authors: Salustiano Eduardo J. , da Costa Kelli M. , Freire-de-Lima Leonardo , Mendonça-Previato Lucia , Previato José O.
Published: February 2020

Multidrug resistance (MDR) in cancer manifests due to cross-resistance to chemotherapeutic drugs with neither structural nor functional relationship, markedly by increased expression and activity of ABC superfamily transporters. Evidences indicate sphingolipids as substrates to ABC proteins in processes such as cell signaling, membrane biosynthesis and inflammation, and products of its biosynthetic route were shown to favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key cell regulator enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Under stress, cells increasede novobiosynthesis of ceramides, which return to sub-toxic levels after assimilation into GlcCer by UGCG. Given that cancer cells seem to mobilize UGCG and increase GSL contents for the clearance of ceramides ultimately contributing to treatment failure, we studied how inhibiting GSL biosynthesis would affect the MDR phenotype of chronic myeloid leukemias. Results indicate that MDR associates to higher expression of UGCG and to a complex GSL profile. Inhibition of this glucosyltransferase greatly reduced GM1 expression, and cotreatment with standard chemotherapeutics sensitized cells leading to mitochondrial membrane potential loss and apoptosis. Despite reducing ABCB1 expression, only the ABCC-mediated efflux activity was affected. Consistently, efflux of C6-ceramide, one byproduct of UGCG downregulation, was reduced after inhibition of ABCC-mediated transport. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, overcoming drug resistance through distinct mechanisms. This work brings more comprehension about the involvement of GSL for chemotherapy failure, and modulation of its contents emerges as an intervention targeted to MDR leukemias.
TERT-mediated induction of MIR500A contributes to tumor invasiveness by targeting Hedgehog pathway
Authors: Bernabé-García Manuel , Martínez-Balsalobre Elena , García-Moreno Diana , García-Castillo Jesús , Revilla-Nuin Beatriz , Blanco-Alcaina Elena , Mulero Victoriano , Alcaraz-Pérez Francisca , Cayuela María L.
Published: February 2020

The classical activity of telomerase (TERT) is to maintain telomere homeostasis, ensuring chromosome stability and cellular proliferation. However, increasing evidences of telomere-independent human TERT functions have been lastly obtained. We report here that TERT directly binds to the TCF binding elements (TBE) located upstream the oncomiRMIR500Ainducing its expression and promoting cancer invasiveness. This function is independent of telomerase activity, since catalytic inactive TERT also inducesMIR500Aexpression and telomerase inhibitors directed against TERT, but not to its RNA componentTERC, inhibit telomerase-inducedMIR500Aexpression and cancer invasiveness. Mechanistically, telomerase-inducedMIR500Adown-regulates key genes of the Hedgehog signaling pathway, namely patched 1 (PTCH1), Gli family zinc finger 3 (GLI3) and cullin 3 (CUL3), increasing tumor invasiveness. Our results show a crucial role of the TERT/MIR500A/Hedgehog axis is tumor aggressiveness, pointing out to the relevance of inhibiting the extracurricular functions of telomerase to fight cancer.
An alternative miRISC targeting a coding mutation site inFOXL2links to granulosa cell tumor
Authors: Shin Eunkyoung , Jin Hanyong , Suh Dae-Shik , Luo Yongyang , Ha Hye-Jeong , Kim Tae Heon , Hahn Yoonsoo , Hyun Seogang , Lee Kangseok , Bae Jeehyeon
Published: February 2020

Recent evidence suggests that animal microRNAs (miRNAs) can target coding sequences (CDSs); however, the pathophysiological importance of such targeting remains unknown. Here, we show that a somatic heterozygous missense mutation (c.402C>G; p.C134W) inFOXL2, a feature shared by virtually all adult-type granulosa cell tumors (AGCTs), introduces a target site for miR-1236, which induces haploinsufficiency of the tumor-suppressorFOXL2. This miR-1236-mediated selective degradation of the variantFOXL2mRNA is preferentially conducted by a distinct miRNA-loaded RNA-induced silencing complex (miRISC) directed by the Argonaute3 (AGO3) and DHX9 proteins. In both patients and mouse model of AGCT, the inversely regulated variantFOXL2abundance with the miR-1236 levels was highly correlated with malignant features of AGCT. Our study provides a molecular basis for understanding the conservedFOXL2CDS mutation-mediated etiology of AGCT, revealing the existence of a previously unidentified mechanism of miRNA-targeting disease-associated mutations in the CDS by forming a non-canonical miRISC.
NFκB dynamics determine the stimulus-specificity of epigenomic reprogramming in macrophages
Authors: Cheng Quen J. , Ohta Sho , Sheu Katherine M. , Spreafico Roberto , Adelaja Adewunmi , Taylor Brooks , Hoffmann Alexander
Published: February 2020

The epigenome defines the cell type, but also shows plasticity that enables cells to tune their gene expression potential to the context of extracellular cues. This is evident in immune sentinel cells such as macrophages, which can respond to pathogens and cytokines with phenotypic shifts that are driven by epigenomic reprogramming1. Recent studies indicate that this reprogramming arises from the activity of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), which binds not only to available enhancers but may producede novoenhancers in previously silent areas of the genome2. Here, we show that NFκB reprograms the macrophage epigenome in a stimulus-specific manner, in response only to a subset of pathogen-derived stimuli. The basis for these surprising differences lies in the stimulus-specific temporal dynamics of NFκB activity. Testing predictions of a mathematical model of nucleosome interactions, we demonstrate through live cell imaging and genetic perturbations that NFκB promotes open chromatin and formation ofde novoenhancers most strongly when its activity is non-oscillatory. Thesede novoenhancers result in the activation of additional response genes. Our study demonstrates that the temporal dynamics of NFκB activity, which encode ligand identity3, can be decoded by the epigenome throughde novoenhancer formation. We propose a mechanistic paradigm in which the temporal dynamics of transcription factors are a key determinant of their capacity to control epigenomic reprogramming, thus enabling the formation of stimulus-specific memory in innate immune sentinel cells.
Are pangolins the intermediate host of the 2019 novel coronavirus (2019-nCoV) ?
Authors: Liu Ping , Jiang Jing-Zhe , Wan Xiu-Feng , Hua Yan , Wang Xiaohu , Hou Fanghui , Chen Jing , Zou Jiejian , Chen Jinping
Published: February 2020

The outbreak of 2019-nCoV pneumonia (COVID-19) in the city of Wuhan, China has resulted in more than 70,000 laboratory confirmed cases, and recent studies showed that 2019-nCoV (SARS-CoV-2) could be of bat origin but involve other potential intermediate hosts. In this study, we assembled the genomes of coronaviruses identified in sick pangolins. The molecular and phylogenetic analyses showed that pangolin Coronaviruses (pangolin-CoV) are genetically related to both the 2019-nCoV and bat Coronaviruses but do not support the 2019-nCoV arose directly from the pangolin-CoV. Our study also suggested that pangolin be natural host ofBetacoronavirus, with a potential to infect humans. Large surveillance of coronaviruses in pangolins could improve our understanding of the spectrum of coronaviruses in pangolins. Conservation of wildlife and limits of the exposures of humans to wildlife will be important to minimize the spillover risks of coronaviruses from wild animals to humans.
Comparing the Fate of Brain Metastatic Breast Cancer Cells in Different Immune Compromised Mice with Cellular Magnetic Resonance Imaging
Authors: Knier Natasha N. , Hamilton Amanda M. , Foster Paula J.
Published: February 2020

Metastasis is the leading cause of mortality in breast cancer patients, with brain metastases becoming increasingly prevalent. Studying this disease is challenging due to the limited experimental models and methods available. Here, we used iron-based cellular MRI to track the fate of a mammary carcinoma cell line (MDA-MB-231-BR)in vivoto characterize the growth of brain metastases in the nude and severely immune-compromised NOD/SCID/ILIIrg−/− (NSG) mouse.

Nude and NSG mice received injections of iron-labeled MDA-MB-231-BR cells. Images were acquired with a 3T MR system and assessed for signal voids and metastases. The percentage of signal voids and the number and volume of metastases were quantified.Ex vivoimaging of the liver, histology, and immunofluorescence labeling was performed.

On day 0, iron-labeled cells were visualized as signal voids throughout the brain. The percentage of voids decreased significantly between day 0 and endpoint. At endpoint, there was no difference in the number of brain metastases or tumour burden in NSG mice compared to nudes. Tumour volumes in nude mice were significantly larger than in NSG mice. Body images indicated that the NSG mice had metastases in the liver, lungs, and lymph nodes.

Characterization of the NSG and nude mouse is necessary to study breast cancer brain metastasisin vivo. Here, we show that the 231BR cell line grew differently in NSG mice compared to nude mice. This work demonstrates the role that imaging can play toward credentialing these models that cannot be done with otherin vitroor histopathologic methods alone.