bluuebunny/crossref_metadata_2025 huggingface dataset:
A Computational Model for Estimating the Progression of COVID-19 Cases in the US West and East Coasts
Authors: Yeo Yao-Yu , Yeo Yao-Rui , Yeo Wan-Jin
Published: March 2020

The ongoing coronavirus disease 2019 (COVID-19) pandemic is of global concern and has recently emerged in the US. In this paper, we construct a stochastic variant of the SEIR model to make a quasi-worst-case scenario prediction of the COVID-19 outbreak in the US West and East Coasts. The model is then fitted to current data and implemented using Runge-Kutta methods. Our computation results predict that the number of new cases would peak around mid-April 2000 and begin to abate by July, and that the number of cases of COVID-19 might be significantly mitigated by having greater numbers of functional testing kits available for screening. The model also showed how small changes in variables can make large differences in outcomes and highlights the importance of healthcare preparedness during pandemics.

Author Summary

Coronavirus disease 2019 (COVID-19) has escalated into a global pandemic and has recently emerged in the US. While some countries have managed to contain COVID-19 efficiently, other countries previously thought to have been well-prepared for outbreaks due to higher living standards and healthcare quality have witnessed an unexpected number of cases. It is currently unclear how the US can cope with the COVID-19 pandemic, especially after mishaps during the initial stages. Our study combines conditions unique to the US and transmission dynamics in regions affected most by COVID-19 to produce a quasi-worse-case scenario of COVID-19 in the US and shows the importance of healthcare preparedness during pandemics.
Estimation of SARS-CoV-2 Infection Prevalence in Santa Clara County
Authors: Yadlowsky Steve , Shah Nigam , Steinhardt Jacob
Published: March 2020

To reliably estimate the demand on regional health systems and perform public health planning, it is necessary to have a good estimate of the prevalence of infection with SARS-CoV-2 (the virus that causes COVID-19) in the population. In the absence of wide-spread testing, we provide one approach to infer prevalence based on the assumption that the fraction of true infections needing hospitalization is fixed and that all hospitalized cases of COVID-19 in Santa Clara are identified.

Our goal is to estimate the prevalence of SARS-CoV-2 infections, i.e. the true number of people currently infected with the virus, divided by the total population size.

Our analysis suggests that as of March 17, 2020, there are 6,500 infections (0.34% of the population) of SARS-CoV-2 in Santa Clara County. Based on adjusting the parameters of our model to be optimistic (respectively pessimistic), the number of infections would be 1,400 (resp. 26,000), corresponding to a prevalence of 0.08% (resp. 1.36%). If the shelter-in-place led to R0 < 1, we would expect the number of infections to remain about constant for the next few weeks. However, even if this were true, we expect to continue to see an increase in hospitalized cases of COVID-19 in the short term due to the fact that infection of SARS-CoV-2 on March 17th can lead to hospitalizations up to 14 days later.
TERL: Classification of Transposable Elements by Convolutional Neural Networks
Authors: da Cruz Murilo Horacio Pereira , Domingues Douglas Silva , Saito Priscila Tiemi Maeda , Paschoal Alexandre Rossi , Bugatti Pedro Henrique
Published: March 2020

Transposable elements (TEs) are the most represented sequences occurring in eukaryotic genomes. They are capable of transpose and generate multiple copies of themselves throughout genomes. These sequences can produce a variety of effects on organisms, such as regulation of gene expression. There are several types of these elements, which are classified in a hierarchical way into classes, subclasses, orders and superfamilies. Few methods provide the classification of these sequences into deeper levels, such as superfamily level, which could provide useful and detailed information about these sequences. Most methods that classify TE sequences use handcrafted features such as k-mers and homology based search, which could be inefficient for classifying non-homologous sequences. Here we propose a pipeline, transposable elements representation learner (TERL), that use four preprocessing steps, a transformation of one-dimensional nucleic acid sequences into two-dimensional space data (i.e., image-like data of the sequences) and apply it to deep convolutional neural networks (CNNs). CNN is used to classify TE sequences because it is a very flexible classification method, given it can be easily retrained to classify different categories and any other DNA sequences. This classification method tries to learn the best representation of the input data to correctly classify it. CNNs can also be accelerated via GPUs to provide fast results. We have conducted six experiments to test the performance of TERL against other methods. Our approach obtained macro mean accuracies and F1-score of 96.4% and 85.8% for the superfamily sequences from RepBase and 95.7% and 91.5% for the order sequences from RepBase respectively. We have also obtained macro mean accuracies and F1-score of 95.0% and 70.6% for sequences from seven databases into superfamily level and 89.3% and 73.9% for the order level respectively. We surpassed accuracy, recall and specificity obtained by other methods on the experiment with the classification of order level sequences from seven databases and surpassed by far the time elapsed of any other method for all experiments. We also show a way to preprocess sequences and prepare train and test sets. Therefore, TERL can learn how to predict any hierarchical level of the TEs classification system, is on average 162 times and four orders of magnitude faster than TEclass and PASTEC respectively and on a real-world scenario obtained better accuracy, recall, and specificity than the other methods.
Distinct functions of tissue-resident and circulating memory Th2 cells in allergic airway disease
Authors: Rahimi Rod A. , Nepal Keshav , Cetinbas Murat , Sadreyev Ruslan I. , Luster Andrew D.
Published: March 2020

Memory CD4+T helper type 2 (Th2) cells are critical in driving allergic asthma pathogenesis, yet the mechanisms whereby tissue-resident memory Th2 cells (Th2 Trm) and circulating memory Th2 cells collaboratein vivoremain unclear. Here, using a house dust mite (HDM) model of allergic asthma and parabiosis, we demonstrate that Th2 Trm and circulating memory Th2 cells perform non-redundant functionsin vivo. Upon HDM re-challenge, circulating memory Th2 cells trafficked into the lung parenchyma and ignited perivascular inflammation to promote eosinophil and CD4+T cell recruitment. In contrast, Th2 Trm proliferated near airways and promoted mucus metaplasia, airway hyper-responsiveness, and airway eosinophil activation. Transcriptional analysis revealed that Th2 Trm and circulating memory Th2 cells share a core Th2 gene signature, but also exhibit distinct transcriptional profiles. Specifically, Th2 Trm express a tissue adaptation signature, including genes involved in regulating and interacting with extracellular matrix. Our findings demonstrate that Th2 Trm and circulating memory Th2 cells are functionally and transcriptionally distinct subsets with unique roles in promoting allergic airway disease.

How memory Th2 cell subsets orchestrate allergic airway inflammation remains unclear. Rahimiet al. use a murine model of allergic asthma and parabiosis to demonstrate that tissue-resident and circulating memory Th2 cells are functionally distinct subsets with unique roles in promoting allergic airway disease.
SCOUT: Single-cell outlier analysis in cancer
Authors: Onzi Giovana Ravizzoni , Faccioni Juliano Luiz , Alvarado Alvaro G. , Bracco Paula Andreghetto , Kornblum Harley I. , Lenz Guido
Published: March 2020

Outliers are often ignored or even removed from data analysis. In cancer, however, single outlier cells can be of major importance, since they have uncommon characteristics that may confer capacity to invade, metastasize, or resist to therapy. Here we present the Single-Cell OUTlier analysis (SCOUT), a resource for single-cell data analysis focusing on outlier cells, and the SCOUT Selector (SCOUTS), an application to systematically apply SCOUT on a dataset over a wide range of biological markers. Using publicly available datasets of cancer samples obtained from mass cytometry and single-cell RNA-seq platforms, outlier cells for the expression of proteins or RNAs were identified and compared to their non-outlier counterparts among different samples. Our results show that analyzing single-cell data using SCOUT can uncover key information not easily observed in the analysis of the whole population.
Dityrosine cross-link trapping of amyloid-β intermediates reveals that self-assembly is required for Aβ-induced cytotoxicity
Authors: Maina Mahmoud B. , Mengham Kurtis , Burra Gunasekhar K. , Al-Hilaly Youssra A. , Serpell Louise C.
Published: March 2020

Multiple chemical reactions, such as the production of reactive oxygen species (ROS) can lead to dityrosine (DiY) formation via the cross-linking of closely spaced tyrosine residues and this can serve as a marker for aging. Amyloid-β (Aβ) has been found to be DiY cross-linked in the brains of AD patients.In vitro,Aβ forms DiY cross-links via metal-catalysed oxidation (Cu2+and H202) (MCO) leading to the formation of fibrils that are resistant to formic acid denaturation. However, copper is well known to influence and enhance self-assembly. Here, to investigate the interplay between self-assembly and DiY cross-linking we have utilised a non-assembly competent variant of Aβ (vAβ). MCO and UV oxidation experiments using vAβ and wild-type Aβ, revealed that DiY cross-linking stabilises, but does not induce or promote Aβ assembly. Cu2+alone, without H202, facilitates the formation and DiY cross-linking of wild-type Aβ into long-lived oligomers. Our work reveals DiY formation halts further Aβ self-assembly. DiY cross-linked Aβ is non-toxic to neuroblastoma cells at all stages of self-assembly in contrast to oligomeric non-cross-linked Aβ. These findings point to a mechanism of toxicity that necessitates continuing self-assembly of the Aβ peptide, whereby trapped DiY Aβ assemblies and assembly incompetent variant Aβ are unable to result in cell death.
PprA interacts with replication proteins and affects their physicochemical properties required for replication initiation inDeinococcus radiodurans
Authors: Maurya Ganesh K. , Misra Hari S.
Published: March 2020

The deletion mutant ofpprA, a gene encoding pleiotropic functions in radioresistant bacteriumDeinococcus radiodurans, showed an increased genomic content and ploidy in chromosome I and chromosome II. We identifiedoriCin chromosome I(oriCI) and demonstrated the sequence specific interaction of deinococcal DnaA (drDnaA) withoriCI. drDnaA and drDnaB showed ATPase activity while drDnaB catalyzed 5′→3′ dsDNA helicase activity. These proteins showed both homotypic and heterotypic interactions. The roles of C-terminal domain of drDnaA inoriCIbinding and its stimulation of ATPase activity were demonstrated. Notably, PprA showed ~2 times higher affinity to drDnaA as compared to drDnaB and attenuated both homotypic and heterotypic interactions of these proteins. Interestingly, the ATPase activity of drDnaA but not drDnaB was inhibited in presence of PprA. These results suggested that PprA influences the physicochemical properties of drDnaA and drDnaB that are required for initiation of DNA replication atoriCIsite in this bacterium.
NeuroRA: A Python Toolbox of Representational Analysis from Multi-modal Neural Data
Authors: Lu Zitong , Ku Yixuan
Published: March 2020

In studies of cognitive neuroscience, multivariate pattern analysis (MVPA) is widely used as it offers richer information than traditional univariate analysis. Representational similarity analysis (RSA), as one method of MVPA, has become an effective decoding method based on neural data by calculating the similarity between different representations in the brain under different conditions. Moreover, RSA is suitable for researchers to compare data from different modalities, and even bridge data from different species. However, previous toolboxes have been made to fit for specific datasets. Here, we develop a novel and easy-to-use toolbox based on Python named NeuroRA for representational analysis. Our toolbox aims at conducting cross-modal data analysis from multi-modal neural data (e.g. EEG, MEG, fNIRS, ECoG, sEEG, neuroelectrophysiology, fMRI), behavioral data, and computer simulated data. Compared with previous software packages, our toolbox is more comprehensive and powerful. By using NeuroRA, users can not only calculate the representational dissimilarity matrix (RDM), which reflects the representational similarity between different conditions, but also conduct a representational analysis among different RDMs to achieve a cross-modal comparison. In addition, users can calculate neural pattern similarity, spatiotemporal pattern similarity (STPS) and inter-subject correlation (ISC) with this toolbox. NeuroRA also provides users with functions performing statistical analysis, storage and visualization of results. We introduce the structure, modules, features, and algorithms of NeuroRA in this paper, as well as examples applying the toolbox in published datasets.
A Novel Method for Calculating Beta Band Burst Durations in Parkinson’s Disease Using a Physiological Baseline
Authors: Anderson RW , Neuville RS , Kehnemouyi YM , Anidi CM , Petrucci MN , Parker JE , Velisar A , Bronte-Stewart H
Published: March 2020

Background

Pathological bursts of neural activity in Parkinson’s disease present as exaggerated subthalamic neuronal oscillations in the 8-30 Hz frequency range and are related to motor impairment.

New Method

This study introduces a novel method for determining burst dynamics using a baseline that matches physiological 1/f spectrum activity. We used resting state local field potentials from people with Parkinson’s disease and a simulated 1/f signal to measure beta burst durations, to demonstrate how tuning parameters (i.e., bandwidth and center frequency) affect burst durations, to compare this with high power threshold methods, and to study the effect of increasing neurostimulation intensities on burst duration.

Results

Burst durations calculated using the Anderson method captured the longest and broadest distribution of burst durations in a pathological beta band compared to previous methods. Mean beta band burst durations were significantly shorter on compared to off neurostimulation (p = 0.011), and their distribution was shifted towards that of the physiological 1/f spectrum during increasing intensities of stimulation.

Comparison with Existing Method

Existing methods of measuring local field potential power either lack temporal specificity to detect bursts (power spectral density diagrams and spectrograms) or include only higher power bursts and portions of the neural signal.

Conclusions

We suggest that this novel method is well suited to quantify the full range of fluctuations in beta band neural activity in the Parkinsonian brain. This method may reveal more relevant feedback biomarkers than averaged beta band power for future closed loop algorithms.

Highlights

A novel method for measuring variability in subthalamic local field potential oscillations in Parkinson’s disease using a physiological baseline of power.

Modeling normal brain activity using a physiological 1/f spectrum.

Burst durations depend on choice of bandwidth and center frequency.

Defining an inert frequency band whose mean burst duration overlap the physiological 1/f spectrum, from which the baseline was determined.

Burst durations progressively shortened during increasing intensities of deep brain stimulation.
Location specific small RNA annealing to the HCV 5’ UTR promotes Hepatitis C Virus replication by favoring IRES formation and stimulating virus translation
Authors: Kunden Rasika D. , Ghezelbash Sarah , Khan Juveriya Q. , Wilson Joyce A.
Published: March 2020

Hepatitis C virus (HCV) genome replication requires annealing of a liver specific small-RNA, miR-122 to 2 sites on 5’ untranslated region (UTR). Annealing has been reported to a) stabilize the genome, b) promote translation, and c) induce the canonical HCV 5’ UTR Internal Ribosome Entry Site (IRES) structure. In this report we identify the relative impact of small RNA annealing on the three functions ascribed to miR-122 and generate a mechanistic model for miR-122 promotion of HCV. First, we identified that perfectly complementary small RNAs that anneal to different locations on the HCV 5’ UTR stimulate replication with varying efficiencies and mapped the region on the HCV genome to which small RNA annealing promotes virus replication. Second, by using a panel of small RNAs that promote with varying efficiencies we link HCV replication induction with translation stimulation and 5’ UTR RNA structure modifications. However, replication promotion was not linked to genome stabilization since all small RNAs tested could stabilize the viral genome regardless of their ability to promote replication. Thus, we propose that miR-122 annealing promotes HCV replication primarily by activating the HCV IRES and stimulating translation, and that miR-122-induced HCV genome stabilization is insufficient alone but enhances virus replication.

Graphical Abstract
Resolving fate and transcriptome of hematopoietic stem cell clones
Authors: Pei Weike , Shang Fuwei , Wang Xi , Fanti Ann-Kathrin , Greco Alessandro , Busch Katrin , Klapproth Kay , Zhang Qin , Quedenau Claudia , Sauer Sascha , Feyerabend Thorsten B. , Höfer Thomas , Rodewald Hans-Reimer
Published: March 2020

Adult bone marrow harbors a mosaic of hematopoietic stem cell (HSC) clones of embryonic origin, and recent work suggests that such clones may have coherent lineage fates. To probe under physiological conditions whether HSC clones with different fates are transcriptionally distinct, we developedPolyloxExpress– a Cre recombinase-dependent DNA substrate for in situ barcoding that allows parallel readout of barcodes and transcriptomes in single cells. We describe differentiation-inactive, multilineage and lineage-restricted HSC clones, find that they reside in distinct regions of the transcriptional landscape of hematopoiesis, and identify corresponding gene signatures. All clone types contain proliferating HSCs, indicating that differentiation-inactive HSCs can undergo symmetric self-renewal. Our work establishes an approach for studying determinants of stem cell fate in vivo and provides molecular evidence for fate coherence of HSC clones.
Explicit feedback and instruction do not change shoulder muscle activity reduction after shoulder fixation
Authors: Maeda Rodrigo S. , Zdybal Julia M. , Gribble Paul L. , Pruszynski J. Andrew
Published: March 2020

Generating pure elbow rotation requires contracting muscles at both the shoulder and elbow joints to counter torques that arise at the shoulder when the forearm rotates (i.e., intersegmental dynamics). Previous work has shown that human participants learn to reduce their shoulder muscle activity if the same elbow movement is performed after the shoulder joint is mechanically locked, which is appropriate because locking the shoulder joint eliminates the torques that arise at the shoulder when the forearm rotates. However, this learning is slow (i.e., it unfolds over hundreds of trials) and incomplete (i.e., shoulder activity is not fully eliminated). Here we investigated whether and how the addition of explicit strategies and biofeedback modulate this type of learning. Three groups of human participants (N = 55) performed voluntary pure elbow rotations using a robotic exoskeleton that permits shoulder and elbow rotation in a horizontal plane. Participants did the task with the shoulder free to move (baseline), then with the shoulder joint locked by the robotic manipulandum (adaptation), and then with the shoulder free to move again (post-adaptation). The first group of participants performed this protocol and received no instructions about what to do after their shoulder was locked. The second group of participants received visual feedback about their shoulder muscle activity after each movement and was instructed to reduce their shoulder activity to zero. The third group of participants also received visual biofeedback, but it was removed part way through the experiment. We found that, although all groups learned, the rate and magnitude of learning was not reliably different across the groups. Taken together, our results suggest that learning new arm dynamics, unlike other motor learning paradigms, unfolds independent of explicit instructions, biofeedback and task instructions.
Opposing influence of top-down and bottom-up input on different types of excitatory layer 2/3 neurons in mouse visual cortex
Authors: Jordan Rebecca , Keller Georg B.
Published: March 2020

Processing in cortical circuits is driven by combinations of cortical and subcortical inputs. These signals are often conceptually categorized as bottom-up input, conveying sensory information, and top-down input, conveying contextual information. Using intracellular recordings in mouse visual cortex, we measured neuronal responses to visual input, locomotion, and visuomotor mismatches. We show that layer 2/3 (L2/3) neurons compute a difference between top-down motor-related input and bottom-up visual flow input. Most L2/3 neurons responded to visuomotor mismatch with either hyperpolarization or depolarization, and these two response types were associated with distinct physiological properties. Consistent with a subtraction of bottom-up and top-down input, visual and motor-related inputs had opposing influence in L2/3 neurons. In infragranular neurons, we found no evidence of a difference-computation and responses were consistent with a positive integration of visuomotor inputs. Our results provide evidence that L2/3 functions as a bidirectional comparator of top-down and bottom-up input.
Disease stage-specific pathogenicity of CD138 (syndecan 1)-expressing T cells in systemic lupus erythematosus
Authors: Liu Lunhua , Takeda Kazuyo , Akkoyunlu Mustafa
Published: March 2020

Objective

To identify and characterize CD138 (syndecan 1)-expressing T cells in SLE-prone mice.

Methods

We characterized CD138-expressing T cells in MRL/Lpr mice by flow cytometry assay and by gene analysis. Functional properties of TCRβ+CD138+ cells were assessed either by activating through TCR or by co-incubating with purified B cells in the presence of auto-antigens. Purified TCRβ+CD138+ cells were adoptively transferred into MRL/Lpr mice and lupus disease was assessed by measuring serum auto-antibodies, proteinuria and by histopathological evaluation of kidney.

Results

We found that the frequency of TCRβ+CD138+ cells was significantly higher in MRL/Lpr mice than in wild-type MRL mice (p < 0.01), and the increase in their numbers correlated with disease severity. Majority of the TCRβ+CD138+ cells were CD4 and CD8 double-negative and 20% were CD4. Compared to TCRβ+CD138− cells, TCRβ+CD138+ cells exhibited central memory phenotype with reduced ability to proliferate, and produce the cytokines IFNγ and IL-17. When co-cultured with B cells, the ability of TCRβ+CD138+ cells to promote plasma cell formation and autoreactive antibody production was dependent on the presence of auto-antigens and CD4 co-receptor expression. Surprisingly, adoptively transferred TCRβ+CD138+ cells slowed down the disease progression in young MRL/Lpr mice but had the opposite effect when DNA was co-administered or when TCRβ+CD138+ cells were transferred into older MRL/Lpr mice with established disease.

Conclusion

Here, we provided evidence for the pathogenic role of CD138-expressing T cells when auto-antigens are exposed to immune system. Thus, monitoring the changes in TCRβ+CD138+ cell-frequency may serve as a tool to assess SLE severity. Moreover, CD138-expressing T cells may be targeted to alleviate lupus progression.
Glucose Production and Glucose Disposal Integrated by an Intrinsic Inverse Coupling in Vivo: hypothesis of inter-organ reflex on glucose regulation
Authors: Liu Nan , Zou Wei , Xing Ying , Zhang Xi , Song Bin , Wang Chen
Published: March 2020

Glucose production (GP) and glucose disposal (Rd) are two decisive and fundamental parameters in glucose turnover and in glucose homeostasis regulation. In conventional theory, GP and Rd were responsive to regulatory factors respectively and independently of each other. Even though GP and Rd responded in reverse to insulin, GP for suppression and Rd for elevation, these inverse alterations used to be attributed to insulin multiple functions both on hepatic GP, directly or indirectly, and on whole-body glucose Rd. However, in the present study, we found GP and Rd were inversely coupled intrinsically no matter which side was the target of insulin by comparison of Rd and GP data pairs between peripheral vein insulin infusion protocol and portal vein insulin infusion protocol in rats. Furthermore, neither circulating NEFA nor HFD induced resistance broke the GP-Rd inverse coupling, but both of them reduced the responses of both GP and Rd to insulin. In conclusion, we provide the evidence that GP and Rd are two coupled parameters in vivo and they alter in reverse simultaneously, the mechanism under which needs further investigation but we tend to believe an inter-organ neural reflex was involved.
Acute gastrointestinal injury in critically ill patients with coronavirus disease 2019 in Wuhan, China
Authors: Sun Jia-Kui , Zou Lei , Liu Ying , Zhang Wen-Hao , Li Jing-Jing , Kan Xiao-Hua , Chen Jiu-Dong , Shi Qian-Kun , Yuan Shou-Tao , Gu Wei , Qi Jian-Wei
Published: March 2020

Background

To investigate the prevalence and outcomes of acute gastrointestinal injury (AGI) in critically ill patients with coronavirus disease 2019 (COVID-19).

Methods

In this clinical retrospective study, demographic data, laboratory parameters, AGI grades, clinical severity and outcomes were collected. The primary endpoints were AGI incidence and 28-day mortality, the secondary endpoints were organ dysfunction and septic shock incidence.

Results

From February 10 to March 10 2020, 83 critically ill patients of 1314 patients with COVID-19 were enrolled. Seventy-two (86.7%) patients had AGI during hospital stay, of them, 30 had AGI grade I, 35 had AGI grade II, 5 had AGI grade III, and 2 had AGI grade IV. The incidence of AGI grade II and above was 50.6%. As of March 16, 40 (48.2%) patients died within 28 days of admission, the median hospital stay was 12.0 days, ranging from 3 days to 27 days. Multiple organ dysfunction syndrome developed in 58 (69.9%) patients, septic shock in 16 (19.3%) patients. Patients with worse AGI grades had worse clinical variables, higher septic shock incidence and 28-day mortality. Sequential organ failure assessment scores (SOFA) (95% CI, 1.374-2.860; P <0.001), white blood cell (WBC) counts (95% CI, 1.037-1.379; P =0.014), duration of mechanical ventilation (MV) (95% CI, 1.020-1.340; P =0.025) were risk factors for the development of AGI grade II and above. Non-survivors were accompanied by higher incidence of AGI grade III to IV than survivors (17.5% vs. 0.0%, P =0.004).

Conclusions

The AGI incidence was 86.7%, and hospital mortality was 48.2% in critically ill patients with COVID-19. SOFA scores, WBC counts, and duration of MV were risk factors for the development of AGI grade II and above. Patients with worse AGI grades had worse clinical severity variables, higher septic shock incidence and 28-day mortality.
Epidemiological Tools that Predict Partial Herd Immunity to SARS Coronavirus 2
Authors: Kamikubo Yasuhiko , Takahashi Atsushi
Published: March 2020

The outbreak of SARS coronavirus 2 (SARS-CoV-2), which occurred in Wuhan, China in December 2019, has caused a worldwide pandemic of coronavirus disease 2019 (COVID-19). However, there is a lack of epidemiological tools to guide effective public policy development. Here we present epidemiological evidence that SARS-CoV-2 S type exited Wuhan or other epicenters in China earlier than L type and conferred partial resistance to the virus on infected populations. Analysis of regional disparities in incidence has revealed that a sharp decline in influenza epidemics is a useful surrogate indicator for the undocumented spread of SARS-CoV-2. The biggest concern in the world is knowing when herd immunity has been achieved and scheduling a time to regain the living activities of each country. This study provides a useful tool to guide the development of local policies to contain the virus.
Myositis associated anti-NT5C1A autoantibody in clinical practice
Authors: Ikenaga Chiseko , Findlay Andrew R. , Goyal Namita A. , Robinson Sarah , Cauchi Jonathan , Hussain Yessar , Wang Leo H. , Kershen Joshua C. , Beson Brent A. , Wallendorf Michael , Bucelli Robert C. , Mozaffar Tahseen , Pestronk Alan , Weihl Conrad C.
Published: March 2020

Objective

To define the diagnostic utility and clinicopathologic features correlating with anti-cytosolic 5′-nucleotidase 1A (NT5C1A) antibody positivity in idiopathic inflammatory myopathies (IIMs).

Methods

4987 patients had anti-NT5C1A status clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 630 of these patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy (IMNM), non-specific myositis, or non-inflammatory muscle diseases.

Results

Anti-NT5C1A was found in 182/287 patients with IBM (63%), 11/53 patients with dermatomyositis (21%), 7/27 patients with antisynthetase syndrome (26%), 9/76 patients with IMNM (12%), 20/84 patients with non-specific myositis (24%), and 6/103 patients with non-inflammatory muscle diseases (6%). The sensitivity and specificity of anti-NT5C1A seropositivity for the diagnosis of IBM was 63% and 85%, respectively. Anti-NT5C1A positive IBM patients had a higher frequency of finger flexion weakness (p<0.01) and their biopsies harbored more COX negative fibers (p=0.04). 18% of anti-NT5C1A negative IBM patients seroconverted to anti-NT5C1A positive on repeat testing.

Conclusions

This is the largest description of patients tested by a clinical diagnostic lab for anti-NT5C1A. We confirm the sensitivity and specificity of anti-NT5C1A for IBM and identified clinicopathologic features in IBM which correlate with anti-NT5C1A status. Notably, anti-NT5C1A testing increased both the diagnostic sensitivity and specificity of IBM when combined with patient age, gender and creatine kinase (CK) level. We propose that future IBM diagnostic criteria include anti-NT5C1A testing.
The current state of COVID-19 in Australia: importation and spread
Authors: Liebig Jessica , Jurdak Raja , El Shoghri Ahmad , Paini Dean
Published: March 2020

Background

The rapid global spread of coronavirus disease (COVID-19) is unprecedented. The outbreak has quickly spread to more than 100 countries reporting over 100,000 confirmed cases. Australia reported its first case of COVID-19 on 25th January 2020 and has since implemented travel restrictions to stop further introduction of the virus.

Methods

We analysed daily global COVID-19 data published by the World Health Organisation to investigate the spread of the virus thus far. To assess the current risk of COVID-19 importation and local spread in Australia we predict international passenger flows into Australia during 2020.

Findings

Our analysis of global data shows that Australia can expect a similar growth rate of reported cases as observed in France and the United States. We identify travel patterns of Australian citizens/residents and foreign travellers that can inform the implementation of new and the alteration of existing travel restrictions related to COVID-19.

Interpretation

Our findings identify the risk reduction potential of current travel bans, based on the proportion of returning travellers to Australia that are residents or visitors. The similarity of the exponential growth in the epidemic curve in Australia to other countries guides forecasts of COVID-19 growth in Australia, and opportunities for drawing lessons from other countries with more advanced outbreaks.
Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer
Authors: Nicolle Rémy , Blum Yuna , Duconseil Pauline , Vanbrugghe Charles , Brandone Nicolas , Poizat Flora , Roques Julie , Bigonnet Martin , Gayet Odile , Rubis Marion , Dou Samir , Elarouci Nabila , Armenoult Lucile , Ayadi Mira , de Reyniès Aurélien , Giovannini Marc , Grandval Philippe , Garcia Stephane , Canivet Cindy , Cros Jérôme , Bournet Barbara , Buscail Louis ,   BACAP Consortium, Moutardier Vincent , Gilabert Marine , Iovanna Juan , Dusetti Nelson
Published: March 2020

BACKGROUND

A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient’s care is the lack of molecular parameters characterizing tumors and allowing a personalized treatment. The goal of this study was to examine whole PDAC transcriptomic profiles to define a signature that would predict aggressiveness and treatment responsiveness better than done until now.

METHODS AND PATIENTS

Tumors were obtained from 76 consecutive resectable (n=40) or unresectable (n=36) tumors. PDAC were transplanted in mice to produce patient-drived xenografts (PDX). PDX were classified according to their histology into five groups, from highly undifferentiated to well differentiated. This classification resulted strongly associated with tumors aggressiveness. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n=598) of resected tumors; ii/ 60 advanced tumors obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumors.

RESULTS

A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumors (e.g. 308 consecutive resected PDAC, HR=0.321 95% CI [0.207;0.5] and 60 locally-advanced or metastatic PDAC, HR=0.308 95% CI [0.113;0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumor response: -0.67, p-value < 0.001).

CONCLUSION

We identified a transcriptomic signature (PAMG) that, unlike all other stratification schemas already proposed, classifies PDAC along a continuous gradient. It can be performed on formalin-fixed paraffin-embedded samples and EUS-guided biopsies showing a strong prognostic value and predicting mFOLFIRINOX responsiveness. We think that PAMG could unify all PDAC preexisting classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.

Trial Registration

The PaCaOmics study is registered atwww.clinicaltrials.govwith registration numberNCT01692873. The validation BACAP study is registered atwww.clinicaltrials.govwith registration numberNCT02818829.
Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala
Authors: Burtscher Johannes , Copin Jean-Christophe , Sandi Carmen , Lashuel Hilal A.
Published: March 2020

Increasing evidence suggests that crosstalk between α-synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinson’s disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinson’s disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology.

Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala.

We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinson’s disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as α-synuclein pathology in male mice.

Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of α-synuclein preformed fibrils into the striatum resulted in pronounced α-synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions.

Our results suggest that early stage α-synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientist to report their negative results in the frame of this model.

Significance statement

We provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinson’s disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of α-synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.
Reconstruction of the Hypothalamo-Neurohypophysial System and Functional Dissection of Magnocellular Oxytocin Neurons in the Brain
Authors: Zhang Bin , Qiu Liyao , Xiao Wei , Ni Hong , Chen Lunhao , Wang Fan , Mai Weihao , Gong Hui , Duan Shumin , Li Anan , Gao Zhihua
Published: March 2020

The hypothalamo-neurohypophysial system (HNS), comprising hypothalamic magnocellular neuroendocrine cells (MNCs) and the neurohypophysis, plays a pivotal role in regulating reproduction and fluid homeostasis by releasing oxytocin and vasopressin into the bloodstream. However, it remains incompletely understood on its structure and whether it contributes to the central actions of oxytocin and vasopressin. Using viral tracing and whole brain imaging, we reconstructed the three-dimensional architecture of the HNS and uncovered that subsets of MNCs collaterally project to multiple extrahypothalamic regions. Moreover, selective activation of magnocellular oxytocin neurons promoted peripheral oxytocin release and facilitated central oxytocin-mediated social interactions. Further, MNCs-released oxytocin in the caudate putamen enhanced locomotion to orchestrate social investigation. Our work reveals the previously unrecognized complexity of the HNS and provides structural and functional evidence for MNCs in coordinating both peripheral and central oxytocin-mediated actions, which will shed light on the mechanistic understanding of oxytocin-related psychiatric diseases.
E proteins orchestrate dynamic transcriptional cascades to suppress ILC2 differentiation
Authors: Peng Vincent , Georgescu Constantin , Bakowska Anna , Qian Liangyue , Wren Jonathan D , Sun Xiao-Hong
Published: March 2020

The basic helix-loop-helix transcription factors collectively called E proteins powerfully suppress the differentiation of group2 innate lymphoid cells from bone marrow and thymic progenitors. Here we investigated the underlying molecular mechanisms using inducible gain and loss of function approaches in ILC2s and their precursors, respectively. Cross-examination of RNA sequencing and ATAC sequencing data obtained at different time points reveals a set of genes which are likely direct targets of E proteins. Consequently, a widespread down-regulation of chromatin accessibility occurs at a later time point, possibly due to the activation of transcriptional repressor genes such asCbfa2t3andJdp2. The large number of genes repressed by gain of E protein function leads to the down-regulation of a transcriptional network important for ILC2 differentiation.

Differentiation of group 2 innate lymphoid cells is forcefully repressed by E protein transcription factors. This report elucidates how E proteins repress a transcriptional network important for ILC2 differentiation by up-regulating the expression of transcriptional repressors.
Identification of lactate as a potential inhibitory factor within epithelial cell supernatant and its effects on type 2 T cell populations
Authors: Hughes Francis , Pavord Ian D , Powell Timothy J
Published: March 2020

Abstract / Short Summary

Epithelial cells have been shown previously to inhibit release of type 2 cytokines from T cells and this process could be important in a type 2-mediated diseases such as asthma. Factors secreted by epithelial cells could regulate inflammatory responses and release an ‘all is well’ signal such that the immune system is controlled. Here we show that lung epithelial cells are able to inhibit IL-2 driven type 2 cytokine release by PBMC cells across a transwell indicating the involvement of soluble mediators. We then fractionate the mediators within the conditioned media using methanol chloroform separation and size fractionation. Inhibitory activity was demonstrated within the polar fraction of supernatant separated by methanol chloroform extraction. We then found that lactate, a component within the polar fraction was able to mediate inhibition of the type 2 cytokines. The inhibitory activity of lactate deserves further study and could play a role in the inhibition of T cell derived cytokines in vivo.
Convective forces increase rostral delivery of intrathecal antisense oligonucleotides in the cynomolgus monkey nervous system
Authors: Sullivan Jenna M. , Mazur Curt , Wolf Daniel A. , Horky Laura , Currier Nicolas , Fitzsimmons Bethany , Hesterman Jacob , Pauplis Rachel , Haller Scott , Powers Berit , Tayefeh Leighla , DeBrosse-Serra Bea , Hoppin Jack , Kordasiewicz Holly , Swayze Eric E. , Verma Ajay
Published: March 2020

Background

The intrathecal (IT) dosing route introduces drugs directly into the CSF to bypass the blood-brain barrier and gain direct access to the CNS. We evaluated the use of convective forces acting on the cerebrospinal fluid as a means for increasing rostral delivery of IT dosed radioactive tracer molecules and antisense oligonucleotides (ASO) in the monkey CNS. We also measured the cerebral spinal fluid (CSF) volume in a group of cynomolgus monkeys.

Methods

There are three studies presented, in each of which cynomolgus monkeys were injected into the IT space with radioactive tracer molecules and/or ASO by lumbar puncture in either a low or high volume. The first study used the radioactive tracer64Cu-DOTA and PET imaging to evaluate the effect of the convective forces. The second study combined the injection of the radioactive tracer99mTc-DTPA and ASO, then used SPECT imaging and ex vivo tissue analysis of the effects of convective forces to bridge between the tracer and the ASO distributions. The third experiment evaluated the effects of different injection volumes on the distribution of an ASO. In the course of performing these studies we also measured the CSF volume in the subject monkeys by Magnetic Resonance Imaging.

Results

It was consistently found that larger bolus dose volumes produced greater rostral distribution along the neuraxis. Thoracic percussive treatment also increased rostral distribution of low volume injections. There was little added benefit on distribution by combining the thoracic percussive treatment with the high-volume injection. The CSF volume of the monkeys was found to be 11.9 ± 1.6 cm3.

Conclusions

These results indicate that increasing convective forces after IT injection increases distribution of molecules up the neuraxis. In particular, the use of high IT injection volumes will be useful to increase rostral CNS distribution of therapeutic ASOs for CNS diseases in the clinic.
CHEER: hierarCHical taxonomic classification for viral mEtagEnomic data via deep leaRning
Authors: Shang Jiayu , Sun Yanni
Published: March 2020

ABSTRARCT

The fast accumulation of viral metagenomic data has contributed significantly to new RNA virus discovery. However, the short read size, complex composition, and large data size can all make taxonomic analysis difficult. In particular, commonly used alignment-based methods are not ideal choices for detecting new viral species. In this work, we present a novel hierarchical classification model named CHEER, which can conduct read-level taxonomic classification from order to genus for new species. By combining k-mer embedding-based encoding, hierarchically organized CNNs, and carefully trained rejection layer, CHEER is able to assign correct taxonomic labels for reads from new species. We tested CHEER on both simulated and real sequencing data. The results show that CHEER can achieve higher accuracy than popular alignment-based and alignment-free taxonomic assignment tools. The source code, scripts, and pre-trained parameters for CHEER are available via GitHub:https://github.com/KennthShang/CHEER.
Medicago truncatula Yellow Stripe-Like7encodes a peptide transporter required for symbiotic nitrogen fixation
Authors: Castro-Rodríguez Rosario , Reguera María , Escudero Viviana , Gil-Díez Patricia , Quintana Julia , Prieto Rosa Isabel , Kumar Rakesh K. , Brear Ella , Grillet Louis , Wen Jiangqi , Mysore Kirunkamar S. , Walker Elsbeth L. , Smith Penelope M. C. , Imperial Juan , González-Guerrero Manuel
Published: March 2020

Yellow Stripe-Like (YSL) proteins are a family of plant transporters typically involved in transition metal homeostasis. The substrate of three of the four YSL clades (clades I, II, and IV) are metal complexes with non-proteinogenic amino acid nicotianamine or its derivatives. No such transport capabilities have been shown for any member of the remaining clade (clade III), which is able to translocate short peptides across the membranes instead. The connection between clade III YSL members and metal homeostasis might have been masked by the functional redundancy characteristic of this family. This might have been circumvented in legumes through neofunctionalization of YSLs to ensure a steady supply of transition metals for symbiotic nitrogen fixation in root nodules. To test this possibility,Medicago truncatulaclade III transporter MtYSL7 has been studied both when the plant was fertilized with ammonium nitrate or when nitrogen had to be provided by endosymbiotic rhizobia within the root nodules. MtYSL7 is a plasma membrane protein expressed in the vasculature and in the nodule cortex. This protein is able to transport short peptides into the cytosol, although none with known metal homeostasis roles. ReducingMtYSL7expression levels resulted in diminished nitrogen fixation rates. In addition, nodules of mutant lines lackingYSL7accumulated more copper and iron, the later the likely result of increased expression in roots of iron uptake and delivery genes. The available data is indicative of a role of MtYSL7, and likely other clade III YSLs, in transition metal homeostasis.

ONE SENTENCE SUMMARY

Medicago truncatulaYSL7 is a peptide transporter required for symbiotic nitrogen fixation in legume nodules, likely controlling transition metal allocation to these organs.