bluuebunny/crossref_metadata_2025 huggingface dataset:
Lymphovenous Anastomosis for Morbidly Obese Patients with Lymphedema
Authors: Yoshida Shuhei , Koshima Isao , Imai Hirofumi , Uchiki Toshio , Sasaki Ayano , Fujioka Yumio , Nagamatsu Shogo , Yokota Kazunori , Yamashita Shuji
Published: May 2020

Background:

Although patients with obesity-induced lymphedema can be treated by weight loss therapy, they find it difficult to lose the required amount of weight. The aims of this study were to clarify the characteristics of the lymphatic vessels in patients with obesity-induced lymphedema and to determine the feasibility and efficacy of lymphovenous anastomosis (LVA) in these patients.

Methods:

Twenty-two patients (44 edematous lower limbs) with a body mass index (BMI) >35 kg/m2 (obese group) and 91 patients with lymphedema (141 edematous lower limbs) and BMI <25 kg/m2 were enrolled as a control group (nonobese group) and underwent LVA. The diameter and depth of lymphatics and the effect of LVA were compared.

Results:

Lymphatics were detectable within 10-mm depth in the nonobese group and the obese group (3.0 ± 1.4 mm versus 3.5 ± 2.1 mm; P < 0.01). The lymphatic diameter was significantly greater in the obese group than in the nonobese group (0.79 ± 0.30 mm versus 0.54 ± 0.22 mm; P < 0.01). There was no significant difference in the rate of improvement in lymphedema after LVA between the nonobese group (9.1% ± 9.2%) and the obese group (8.9% ± 7.3%; P = 0.84). There was no correlation between the improvement rate of lymphedema and that of BMI in the obese group (P = 0.57).

Conclusions:

LVA is a feasible procedure even in morbidly obese patients. Considering that substantial weight loss is a difficult and time-consuming task for patients, LVA combined with not gaining weight is a good option for these patients.
A Comparison of the Visual Field Parameters of SITA Faster and SITA Standard Strategies in Glaucoma
Authors: Lavanya Raghavan , Riyazuddin Mohammed , Dasari Srilakshmi , Puttaiah Narendra K. , Venugopal Jayasree P. , Pradhan Zia S. , Devi Sathi , Sreenivasaiah Shruthi , Ganeshrao Shonraj B. , Rao Harsha L.
Published: May 2020

Purpose:

To compare the visual field (VF) parameters of the new Swedish Interactive Thresholding Algorithm (SITA), SITA Faster (SFR) with that of SITA Standard (SS) on the Humphrey Field Analyzer.

Methods:

Ninety-seven eyes of 97 subjects (63 glaucoma, 26 glaucoma suspects, and 8 normal eyes) underwent VF examination with SFR and SS strategies on the same day in random order. Agreement in VF parameters between SFR and SS strategies was assessed by Bland and Altman plots. In addition, some subjects underwent a second VF examination with SFR strategy to evaluate its test-retest variability.

Results:

The median test duration of SS strategy was 6 minutes 14 seconds, whereas SFR was 2 minutes 49 seconds (55% shorter, P<0.001). Median mean deviation (−7.3 vs. −7.6 dB, P=0.73) and VF index (88 vs. 88%, P=0.32) were similar between the 2 strategies, whereas pattern standard deviation was significantly higher (4.8 vs. 4.7 dB, P=0.01) with SS strategy. Overall average threshold sensitivity and Garway-Heath sector-wise threshold sensitivities were similar between the 2 strategies except for the nasal sector where SFR strategy had higher sensitivity (26 vs. 25 dB, P=0.02). Bland-Altman plots showed the mean difference in all VF parameters between the SS and SFR strategies were small (ranging from −1.0 dB for the nasal sector to −0.01 dB for superotemporal sector sensitivity). The test-retest variability of VF parameters with SFR strategy was low.

Conclusions:

VF parameters with SFR showed good agreement with that of SS strategy. This, combined with low test-retest variability, suggests that SFR can be considered for diagnosis and monitoring of glaucoma.
Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology
Authors: Lim Bryant , Sproule Beth A. , Zahra Zarin , Sunderji Nadiya , Kennedy Sidney H. , Rizvi Sakina J.
Published: May 2020

Benzodiazepines are frequently prescribed on an ongoing basis to individuals with depression, mainly to alleviate anxiety or insomnia, despite current guideline recommendations that continuous use should not exceed 4 weeks. Currently, there are no efficacy trials published beyond 8 weeks. Several antidepressant trials demonstrate that the concomitant use of a benzodiazepine is associated with poorer depressive outcomes and functional status; however, it is unclear why this is the case. Patients with depression receiving a benzodiazepine may reflect a more ill or high anxiety group, although even within anxiety disorders, the use of a benzodiazepine is associated with poorer outcomes. The neuroadaptive consequences of long-term benzodiazepine use may be a factor underlying these findings. Chronic benzodiazepine use results in decreased gamma-aminobutyric acid and monoaminergic function, as well as interference with neurogenesis, which are all purported to play a role in antidepressant efficacy. This review will discuss the oppositional neuropharmacological interactions between chronic benzodiazepine use and antidepressant mechanism of action, which could result in reduced antidepressant efficacy and function in depression.
Darunavir inhibits Cryptococcus neoformans/Cryptococcus gattii species complex growth and increases the susceptibility of biofilms to antifungal drugs
Authors: Brilhante Raimunda Sâmia Nogueira , Silva José Alexandre Telmos , Araújo Géssica dos Santos , Pereira Vandbergue Santos , Gotay Wilker Jose Perez , Oliveira Jonathas Sales de , Guedes Glaucia Morgana de Melo , Pereira-Neto Waldemiro Aquino , Castelo-Branco Débora de Souza Collares Maia , Cordeiro Rossana de Aguiar , Sidrim José Júlio Costa , Rocha Marcos Fábio Gadelha
Published: May 2020

Introduction.Cryptococcusspecies are pathogens commonly associated with cases of meningoencephalitis in individuals who are immunosuppressed due to AIDS.

Aim.The aim was to evaluate the effects of the antiretroviral darunavir alone or associated with fluconazole, 5-flucytosine and amphotericin B against planktonic cells and biofilms ofCryptococcusspecies.

Methodology.Susceptibility testing of darunavir and the common antifungals against 12 members of theCryptococcus neoformans/Cryptococcus gattiispecies complex was evaluated by broth microdilution. The interaction between darunavir and antifungals against planktonic cells was tested by a checkerboard assay. The effects of darunavir against biofilm metabolic activity and biomass were evaluated by the XTT reduction assay and crystal violet staining, respectively.

Results.Darunavir combined with amphotericin B showed a synergistic interaction against planktonic cells. No antagonistic interaction was observed between darunavir and the antifungals used. AllCryptococcusspecies strains were strong biofilm producers. Darunavir alone reduced biofilm metabolic activity and biomass when added during and after biofilm formation (P<0.05). The combination of darunavir with antifungals caused a significant reduction in biofilm metabolic activity and biomass when compared to darunavir alone (P<0.05).

Conclusion.Darunavir presents antifungal activity against planktonic cells ofCryptococcusspecies and synergism with amphotericin B. In addition, darunavir led to reduced biofilm formation and showed activity against mature biofilms ofCryptococcusspecies. Activity of the antifungals against mature biofilms was enhanced in the presence of darunavir.
Genetic diversity of influenza A viruses circulating in Bulgaria during the 2018–2019 winter season
Authors: Korsun Neli , Daniels Rodney , Angelova Svetla , Ermetal Burcu , Grigorova Iliyana , Voleva Silvia , Trifonova Ivelina , Kurchatova Anna , McCauley John
Published: May 2020

Introduction. Influenza viruses evolve rapidly and change their antigenic characteristics, necessitating biannual updates of flu vaccines.

Aim. The aim of this study was to characterize influenza viruses circulating in Bulgaria during the 2018/2019 season and to identify amino acid substitutions in them that might impact vaccine effectiveness.

Methodology. Typing/subtyping of influenza viruses were performed using real-time Reverse Transcription-PCR (RT-PCR) and results of phylogenetic and amino acid sequence analyses of influenza strains are presented.

Results. A(H1N1)pdm09 (66 %) predominated over A(H3N2) (34 %) viruses, with undetected circulation of B viruses in the 2018/2019 season. All A(H1N1)pdm09 viruses studied fell into the recently designated 6B.1A subclade with over 50 % falling in four subgroups: 6B.1A2, 6B.1A5, 6B.1A6 and 6B.1A7. Analysed A(H3N2) viruses belonged to subclades 3C.2a1b and 3C.2a2. Amino acid sequence analysis of 36 A(H1N1)pdm09 isolates revealed the presence of six–ten substitutions in haemagglutinin (HA), compared to the A/Michigan/45/2015 vaccine virus, three of which occurred in antigenic sites Sa and Cb, together with four–nine changes at positions in neuraminidase (NA), and a number of substitutions in internal proteins. HA1 D222N substitution, associated with increased virulence, was identified in two A(H1N1)pdm09 viruses. Despite the presence of several amino acid substitutions, A(H1N1)pdm09 viruses remained antigenically similar to the vaccine virus. The 28 A(H3N2) viruses characterized carried substitutions in HA, including some in antigenic sites A, B, C and E, in NA and internal protein sequences.

Conclusion. The results of this study showed the genetic diversity of circulating influenza viruses and the need for continuous antigenic and molecular surveillance.
Use of vestibular galvanic stimulation for correction of the position and of the gaze in a flight simulator
Authors: Vega Rosario , Gordillo Jorge , Alexandrov Vladimir , Alexandrova Tamara , Soto Enrique
Published: May 2020

Galvanic Vestibular Stimulation(GVS) induce the sensation of movement in subjects in flight simulators and in cosmonauts, creating a cognitive simulation of movement. The system consists of a control unit, a function generator, and a power amplifier. GVS is capable of activating the neurons of the vestibular system and inducing the sensation of movement. When applied in coordination with a flight simulation program GVS modifies the eye movement control responses, electrically activating the vestibular-ocular, vestibule-colic, and vestibule-spinal reflexes. The ultimate goal of this type of stimulation is to generate augmented reality in the pilots during training or potentially also during a flight in microgravity.
Flexible comparison of batch correction methods for single-cell RNA-seq using BatchBench
Authors: Chazarra-Gil Ruben , van Dongen Stijn , Kiselev Vladimir Yu , Hemberg Martin
Published: May 2020

As the cost of single-cell RNA-seq experiments has decreased, an increasing number of datasets are now available. Combining newly generated and publicly accessible datasets is challenging due to non-biological signals, commonly known as batch effects. Although there are several computational methods available that can remove batch effects, evaluating which method performs best is not straightforward. Here we present BatchBench (https://github.com/cellgeni/batchbench), a modular and flexible pipeline for comparing batch correction methods for single-cell RNA-seq data. We apply BatchBench to eight methods, highlighting their methodological differences and assess their performance and computational requirements through a compendium of well-studied datasets. This systematic comparison guides users in the choice of batch correction tool, and the pipeline makes it easy to evaluate other datasets.
Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets
Authors: Castle Brian T. , Dock Carissa , Hemmat Mahya , Kline Susan , Tignanelli Christopher , Rajasingham Radha , Masopust David , Provenzano Paolo , Langlois Ryan , Schacker Timothy , Haase Ashley , Odde David J.
Published: May 2020

Effective therapies for COVID-19 are urgently needed. Presently there are more than 800 COVID-19 clinical trials globally, many with drug combinations, resulting in an empirical process with an enormous number of possible combinations. To identify the most promising potential therapies, we developed a biophysical model for the SARS-CoV-2 viral cycle and performed a sensitivity analysis for individual model parameters and all possible pairwise parameter changes (162= 256 possibilities). We found that model-predicted virion production is fairly insensitive to changes in most viral entry, assembly, and release parameters, but highly sensitive to some viral transcription and translation parameters. Furthermore, we found a cooperative benefit to pairwise targeting of transcription and translation, predicting that combined targeting of these processes will be especially effective in inhibiting viral production.
RepeatProfiler: a pipeline for visualization and comparative analysis of repetitive DNA profiles
Authors: Negm S. , Greenberg A. , Larracuente A.M. , Sproul J.S.
Published: May 2020

Study of DNA repeats in model organisms highlights the role of repetitive DNA in many processes that drive genome evolution and phenotypic change. Because repetitive DNA is much more dynamic than single-copy DNA, repetitive sequences can reveal signals of evolutionary history over short time scales that may not be evident in sequences from slower-evolving genomic regions. Many tools for studying repeats are directed toward organisms with existing genomic resources, including genome assemblies and repeat libraries. However, signals in repeat variation may prove especially valuable in disentangling evolutionary histories in diverse non-model groups, for which genomic resources are limited. Here we introduceRepeatProfiler, a tool for generating, visualizing, and comparing repetitive DNA profiles from low-coverage, short-read sequence data.RepeatProfilerautomates the generation and visualization of repetitive DNA coverage depth profiles and allows for statistical comparison of profile shape across samples. In addition,RepeatProfilerfacilitates comparison of profiles by extracting signal from sequence variants across profiles which can then be analyzed as molecular morphological characters using phylogenetic analysis. We validateRepeatProfilerwith data sets from ground beetles (Bembidion), flies (Drosophila), and tomatoes (Solanum). We highlight the potential of repetitive DNA profiles as a high-resolution data source for studies in species delimitation, comparative genomics, and repeat biology.
Protective Effects of Edaravone Against Hypoxia-Induced Lethality in Male Swiss Albino Mice
Authors: Shaki Fatemeh , Mokhtaran Mina , Raei Maedeh , Shamshirian Amir , Eslami Shahram , Shamshirian Danial , Ebrahimzadeh Mohammad Ali
Published: May 2020

Edaravone has been recently used for the treatment of acute cerebral infarction. However, there is no data on the protective effects of this drug against hypoxia-induced lethality. Here, we aimed to evaluate the protective effects of edaravone against hypoxia-induced lethality and oxidative stress in mice through three experimental models of hypoxia.

Materials and Methods

male Swiss albino mice were randomly housed in groups of 10. Mice received single i.p. injections of edaravone for four consecutive days. Three experimental models of hypoxia: asphyctic, circulatory, and haemic were applied in this study. Oxidative stress, lipid peroxidation and glutathione content were assessed after hypoxia induction.

Results

Significant protective activities were observed in all models of hypoxia. Antihypoxic activities were highly significant in asphytic and circulatory hypoxia. These effects were dose-dependent. Edaravone, at 5 mg kg−1, showed statistically significant activities concerning the control groups. Edaravone significantly prolonged the latency for death. At 2.5 mg kg−1, it prolonged survival time (26.08 ± 0.79 min). This effect was statistically significant (P<0.05). Also, edaravone significantly inhibited hypoxia-induced oxidative stress (lipid peroxidation and glutathione oxidation) in three models of hypoxia.

Conclusions

Edaravone showed an excellent protective effect against hypoxia in all tested models and decreased the oxidative stress in the brain tissue of hypoxic mice. Notably, results showed significant and dose-dependent effects on the models of asphytic and circulatory hypoxia. The antioxidant activity itself might be a proposed mechanism for the antihypoxic activities of this drug.

Impact statement

This study provides a novel proof-of-concept for a FDA approved drug, which will open a new area of research in the field and drug repurposing.
Sex and Power: sexual dimorphism in trait variability and its eco-evolutionary and statistical implications
Authors: Zajitschek S.R.K. , Zajitschek F. , Bonduriansky R. , Brooks R.C. , Cornwell W. , Falster D.S. , Lagisz M. , Mason J. , Senior A. M. , Noble D. A. W. , Nakagawa S.
Published: May 2020

Biomedical and clinical sciences are experiencing a renewed interest in the fact that males and females differ in many anatomic, physiological, and behavioral traits. Sex differences in trait variability, however, are yet to receive similar recognition. In medical science, mammalian females are assumed to have higher trait variability due to estrous cycles (the ‘estrus-mediated variability hypothesis’); historically in biomedical research, females have been excluded for this reason. Contrastingly, evolutionary theory and associated data support the ‘greater male variability hypothesis’. Here, we test these competing hypotheses in 218 traits measured in >26,900 mice, using meta-analysis methods. Neither hypothesis could universally explain patterns in trait variability. Sex-bias in variability was trait-dependent. While greater male variability was found in morphological traits, females were much more variable in immunological traits. Sex-specific variability has eco-evolutionary ramifications including sex-dependent responses to climate change, as well as statistical implications including power analysis considering sex difference in variance.
Decomposition in mixed beech forests in the south-western Alps under severe summer drought
Authors: Jourdan Marion , Hättenschwiler Stephan
Published: May 2020

Climate and plant litter diversity are major determinants of carbon (C) and nitrogen (N) cycling rates during decomposition. Yet, how these processes will be modified with combined changes in climate and biodiversity is poorly understood. With a multisite field experiment, we studied the interactive effects of summer drought (using rainout shelters) and tree species mixing in beech forests in the French Alps. Forests included monospecific stands ofFagus sylvatica, Abies alba, andQuercus pubescensand two-species mixtures composed of beech and one of the other species. We hypothesized (1) negative effects of summer drought on C and N loss during decomposition and (2) mitigation of these negative effects in mixed tree species stands. Litter lost 35% of initial C, and 15% of N on average across all sites and litter types over 30 months of decomposition. Summer drought consistently, but weakly, reduced C loss but had no effect on N loss. Tree species mixing did not alter drought effects on decomposition but had non-additive effects on C and N loss, which were dominated by direct litter mixing rather than indirect tree canopy effects. Our data suggest relatively small drought effects on decomposition, possibly because process rates are generally slow during summer and because microsite variability exceeds that in response to rain exclusion. The dominant contribution of litter mixing to biodiversity effects supports the importance of microsite conditions for C and N dynamics during decomposition, which should be accounted for more explicitly in climate and biodiversity change predictions.
Precise detection of Acrs in prokaryotes using only six features
Authors: Dong Chuan , Pu Dong-Kai , Ma Cong , Wang Xin , Wen Qing-Feng , Zeng Zhi , Guo Feng-Biao
Published: May 2020

Anti-CRISPR proteins (Acrs) can suppress the activity of CRISPR-Cas systems. Some viruses depend on Acrs to expand their genetic materials into the host genome which can promote species diversity. Therefore, the identification and determination of Acrs are of vital importance. In this work we developed a random forest tree-based tool, AcrDetector, to identify Acrs in the whole genomescale using merely six features. AcrDetector can achieve a mean accuracy of 99.65%, a mean recall of 75.84%, a mean precision of 99.24% and a mean F1 score of 85.97%; in multi-round, 5-fold cross-validation (30 different random states). To demonstrate that AcrDetector can identify real Acrs precisely at the whole genome-scale we performed a cross-species validation which resulted in 71.43% of real Acrs being ranked in the top 10. We applied AcrDetector to detect Acrs in the latest data. It can accurately identify 3 Acrs, which have previously been verified experimentally. A standalone version of AcrDetector is available athttps://github.com/RiversDong/AcrDetector. Additionally, our result showed that most of the Acrs are transferred into their host genomes in a recent stage rather than early.
Discovery of positive and purifying selection in metagenomic time series of hypermutator microbial populations
Authors: Maddamsetti Rohan , Grant Nkrumah A.
Published: May 2020

A general method to infer both positive and purifying selection during the real-time evolution of hypermutator pathogens would be broadly useful. To this end, we introduce a simple test to infer mode of selection (STIMS) from metagenomic time series of evolving microbial populations. We test STIMS on metagenomic data generated by simulations of bacterial evolution, and on metagenomic data spanning 62,750 generations of Lenski’s long-term evolution experiment withEscherichia coli(LTEE). In both cases, STIMS recovers signals of positive and purifying selection on gold standard sets of genes. Using STIMS, we find strong evidence of ongoing positive selection on key regulators of theE. coligene regulatory network, even in some hypermutator populations. STIMS also detects positive selection on regulatory genes in hypermutator populations ofPseudomonas aeruginosathat adapted to subinhibitory concentrations of colistin – an antibiotic of last resort – for just twenty-six days of laboratory evolution. Our results show that the fine-tuning of gene regulatory networks is a general mechanism for rapid and ongoing adaptation. The simplicity of STIMS, together with its intuitive visual interpretation, make it a useful test for positive and purifying selection in metagenomic data sets that track the evolution of hypermutator populations in real-time.
DNA methylation mediated downregulation of histone H3 variant H3.3 affects cell proliferation contributing to the development of HCC
Authors: Reddy Divya , Bhattacharya Saikat , Shah Sanket , Rashid Mudasir , Gupta Sanjay
Published: May 2020

H3.3 variant is a versatile histone important for development and disease. We report a DNA methylation dependent decrease of histone H3 variant H3.3 in hepatocellular carcinoma (HCC) development and an increase in the level of the H3.2 variant. The loss of H3.3 correlates with a decrease in the histone PTMs associated with active transcription. The overexpression of H3.3 and H3.2 did not affect global PTMs and cell physiology, probably owing to the deregulation of specific histone chaperones CAF-1 (for H3.2) and HIRA (for H3.3) that we observed in HCC. Notably, upon P150 (CAF-1 subunit) knockdown in HCC cell lines, a cell cycle arrest in S-phase was observed, possibly due to the decrease in the histone levels necessary for DNA packaging. Furthermore, H3.3 knockdown in a preneoplastic liver cell line led to an increase in cell proliferation and a decreased transcription of tumor suppressor genes, recapitulating the tumor cell phenotype. Importantly, our data suggest that the use of DNA Methyl Transferase (DNMT) and Histone Deacetylase (HDAC) inhibitors to restore the expression of H3.3 and the altered chromatin state for the better clinical management of the disease.
Identification and physiological significance of temporal NFκB signaling codewords deployed by macrophages to classify immune threats
Authors: Taylor Brooks , Adelaja Adewunmi , Liu Yi , Luecke Stefanie , Hoffmann Alexander
Published: May 2020

Acute and chronic inflammatory pathologies involve misregulation of macrophage functions. Physiologically, macrophages are immune sentinels that initiate inflammatory responses via the transcription factor NFκB. The temporal pattern of NFκB activity determines which genes are expressed, suggesting that a temporal signaling code specifies a stimulus-appropriate immune response. To identify the signaling codewords, we developed tools to enable high-throughput analysis of live, primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features that constitute codewords that convey stimulus information to the nucleus. In particular, “oscillatory” trajectories are a hallmark of the responses to host cytokine TNF. Remarkably, examining macrophages derived from a systemic autoimmune disease model suggests that confusion of two NFκB signaling codewords, and thus miscoding of TNF as a pathogen-derived stimulus, may underlie sporadic inflammatory pathology. Overall, this study identifies six codewords of the temporal NFκB signaling code for classifying immune threats and demonstrates their biological significance.
Functional analysis of theteosinte branched 1gene in the tetraploid switchgrass (Panicum virgatum L.) by CRISPR/Cas9-directed mutagenesis
Authors: Liu Yang , Wang Weiling , Yang Bing , Currey Christopher , Fei Shui-zhang
Published: May 2020

Tillering is an important biomass yield component trait in switchgrass (Panicum virgatum L.).Teosinte branched 1(tb1)/Branched 1(BRC1) gene is a known regulator for tillering/branching in several plant species; however, its role on tillering in switchgrass remains unknown. Here, we report physiological and molecular characterization of mutants created by CRISPR/Cas9. We successfully obtained non-chimericPvtb1aandPvtb1bmutants from chimeric T0 mutants using nodal culture. The biallelicPvtb1a-Pvtb1bmutant plants produced significantly more tillers and higher fresh weight biomass than the wild-type plants. The increased tiller production in the mutant plants resulted primarily from hastened outgrowth of lower axillary buds. Increased tillers were also observed in transgene-free T1 monoallelic mutants for eitherPvtb1a-Pvtb1borPvtb1bgene alone, suggestingPvtb1genes act in a dosage-dependent manner. Transcriptome analysis showed 831 genes were differentially expressed in thePvtb1a-Pvtb1bdouble knockdown mutant. Gene Ontology analysis revealed downregulation ofPvtb1genes affected multiple biological processes, including transcription, flower development, cell differentiation, and stress/defense responses in edited plants. This study demonstrates thatPvtb1genes play a pivotal role in tiller production as a negative regulator in switchgrass and provides opportunities for further research aiming to elucidate the molecular pathway regulating tillering in switchgrass.

Highlight

Solid non-chimeric mutants were successfully isolated from CRISPR/Cas9-induced chimeric mutants using nodal culture.Teosinte branched 1(tb1) genes are involved in various pathways to regulate tillering in switchgrass.
Integrated hiPSC-based liver and heart microphysiological systems predict unsafe drug-drug interaction
Authors: Lee-Montiel Felipe T. , Laemmle Alexander , Dumont Laure , Lee Caleb S. , Huebsch Nathaniel , Charwat Verena , Okochi Hideaki , Hancock Matthew J. , Siemons Brian , Boggess Steven C. , Goswami Ishan , Miller Evan W. , Willenbring Holger , Healy Kevin
Published: May 2020

Microphysiological systems (MPSs) mimicking human organ functionin vitroare an emerging alternative to conventional cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS—both built with the same hiPSC line—to study drug-drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish functional integration of isogenic hiPSC-based liver and cardiac MPSs, which allows screening for DDI, and thus drug efficacy and toxicity, in the same genetic background.
Timing of fruiting rather than topography determines the direction of vertical seed dispersal by mammals and birds
Authors: Tsunamoto Y. , Koike S. , Tayasu I. , Masaki T. , Kato S. , Kikuchi S. , Nagamitsu T. , Haraguchi T. , Naganuma T. , Naoe S.
Published: May 2020

Vertical seed dispersal toward higher or lower altitudes has been recognized as one of the critical processes for plants to escape from climate change. Studies exploring vertical seed dispersal are scarce, preventing the prediction of future vegetation dynamics. In the present study, we show that the timing of fruiting, rather than topography, determines the direction of vertical seed dispersal by mammals and birds across mountains in central Japan. We found strong uphill seed dispersal of summer fruiting cherry and weak downhill seed dispersal of summer-to-autumn fruiting cherry, irrespective of mountains and animals. The ascent or descent of animals, following the altitudinal gradients in food plant phenology in the temperate zone, was considered to be a driver of the biased seed dispersal. We found that megafauna (i.e., bears) intensively dispersed seeds vertically. The results suggest that the timing of fruiting and megafauna strongly affect whether animal-dispersed temperate plants can maintain their populations under climate change.
Emergence and Propagation of Epistasis in Metabolic Networks
Authors: Kryazhimskiy Sergey
Published: May 2020

Epistasis is often used to probe functional relationships between genes, and it plays an important role in evolution. However, we lack theory to understand how functional relationships at the molecular level translate into epistasis at the level of whole-organism phenotypes, such as fitness. Here, I derive two rules for how epistasis between mutations with small effects propagates from lower-to higher-level phenotypes in a hierarchical metabolic network with first-order kinetics and how such epistasis depends on topology. Most importantly, weak epistasis at a lower level may be distorted as it propagates to higher levels. Computational analyses show that epistasis in more realistic models likely follows similar, albeit more complex, patterns. These results suggest that pairwise inter-gene epistasis should be common and it should generically depend on the genetic background and environment. Furthermore, the epistasis coefficients measured for high-level phenotypes may not be sufficient to fully infer the underlying functional relationships.
Social structure defines spatial transmission of African swine fever in wild boar
Authors: Pepin Kim M. , Golnar Andrew , Podgórski Tomasz
Published: May 2020

Spatial spread of infectious disease is determined by spatial and social processes such as animal space use and family group structure. Yet, impacts of social processes on spatial spread remain poorly understood and estimates of spatial transmission kernels (STKs) often exclude social structure. Understanding impacts of social structure on STKs is important for obtaining robust inferences for policy decisions and optimizing response plans.

We fit spatially-explicit transmission models with different assumptions about contact structure to African swine fever virus (ASFv) surveillance data from Eastern Poland from 2014-2015 and evaluated how social structure affected inference of STKs and spatial spread.

The model with social structure provided better inference of spatial spread, predicted that ∼80% of transmission events occurred within family groups, and that transmission was weakly female-biased (other models predicted weakly male-biased transmission). In all models, most transmission events were within 1.5 km, with some rare events at longer distances. Effective reproductive numbers were between 1.1 and 2.5 (maximum values between 4 and 8).

Social structure can modify spatial transmission dynamics. Accounting for this additional contact heterogeneity in spatial transmission models could provide more robust inferences of STKs for policy decisions, identify best control targets, and improve transparency in model uncertainty.
Inferring TF activities and activity regulators from gene expression data with constraints from TF perturbation data
Authors: Ma Cynthia , Brent Michael R.
Published: May 2020

Background

The activity of a transcription factor (TF) in a sample of cells is the extent to which it is exerting its regulatory potential. Many methods of inferring TF activity from gene expression data have been described, but due to the lack of appropriate large-scale datasets, systematic and objective validation has not been possible until now.

Results

Using a new dataset, we systematically evaluate and optimize the approach to TF activity inference in which a gene expression matrix is factored into a condition-independent matrix of control strengths and a condition-dependent matrix of TF activity levels. These approaches require a TF network map, which specifies the target genes of each TF, as input. We evaluate different approaches to building the network map and deriving constraints on the matrices. We find that such constraints are essential for good performance. Constraints can be obtained from expression data in which the activities of individual TFs have been perturbed, and we find that such data are both necessary and sufficient for obtaining good performance. Remaining uncertainty about whether a TF activates or represses a target is a major source of error. To a considerable extent, control strengths inferred using expression data from one growth condition carry over to other conditions. As a result, the control strength matrices derived here can be used for other applications. Finally, we apply these methods to gain insight into the upstream factors that regulate the activities of four yeast TFs: Gcr2, Gln3, Gcn4, and Msn2. Evaluation code and data available athttps://github.com/BrentLab/TFA-evaluation

Conclusions

When a high-quality network map, constraints, and perturbation-response data are available, inferring TF activity levels by factoring gene expression matrices is effective. Furthermore, it provides insight into regulators of TF activity.
“Temporal control of tumor growth in nocturnal mammals: impact of the circadian system”
Authors: Wagner Paula M. , Prucca César G. , Velázquez Fabiola N. , Alderete Lucas Sosa , Caputto Beatriz L. , Guido Mario E.
Published: May 2020

Glioblastoma multiforme is the most aggressive brain tumor; however, little is known about the impact of the circadian system on the tumor formation, growth and treatment. We investigated day/night differences in tumor growth after injecting A530 glioma cells isolated from malignant peripheral nerve sheath tumor of NPcis (Trp53+/-;Nf1+/-)mice. Tumors generated in the sciatic nerve zone of C57BL/6 mice injected early at night in the light/dark cycle or in constant darkness, showed higher growth rates than in animals injected diurnally. Similar nocturnal increases were observed when injecting B16 melanoma cells or when mice received knocked-down clock geneBmal1 cells. Moreover, treatment with a low-dose of the proteasome inhibitor Bortezomib (0.5 mg/kg) in tumor-bearing animals, displayed higher efficacy when administered at night. Results suggest the existence of a precise temporal control of tumor growth and of drug efficacy in which the host state and susceptibility are critical.
Collective protection and transport in entangled biological and robotic active matter
Authors: Ozkan-Aydin Yasemin , Goldman Daniel I. , Bhamla M. Saad
Published: May 2020

Living systems at all scales aggregate in large numbers for a variety of functions including mating, predation, and survival. The majority of such systems consist of unconnected individuals that collectively flock, school or swarm. However some aggregations involve physically entangled individuals, which can confer emergent mechanofunctional material properties to the collective. Here we study in laboratory experiments and rationalize in theoretical and robotic models the dynamics of physically entangled and motile self-assemblies of centimeter long California blackworms (L. Variegatus). Thousands of individual worms form braids with their long, slender and flexible bodies to make a three-dimensional, soft and shape-shifting ‘blob’. The blob behaves as a living material capable of mitigating damage and assault from environmental stresses through dynamic shape transformations, including minimizing surface area for survival against desiccation and enabling transport (negative thermotaxis) from hazardous environments (like heat). We specifically focus on the locomotion of the blob to understand how an amorphous entangled ball of worms is able to break symmetry to move across a substrate. We hypothesize that the collective blob displays rudimentary differentiation of function across itself, which when combined with entanglement dynamics facilitates directed persistent blob locomotion. To test this, we develop robophysical blobs, which display emergent locomotion in the collective without sophisticated control or programming of any individual robot. The emergent dynamics of the living functional blob and robophysical model can inform the rational design of exciting new classes of adaptive mechanofunctional living materials and emergent swarm robotics.

Significance Statement

Living organisms form collectives across all scales, from bacteria to whales, enabling biological functions not accessible by individuals alone. In a few small cases, the individuals are physically connected to each other, forming to a new class of entangled active matter systems with emergent mechanofunctionalities of the collective. Here, we describe the dynamics of macroscopic aquatic worms that braid their long, soft bodies to form large entangled worm blobs. We discover that the worm blob behaves as a living material to undergo dynamic shape transformations to reduce evaporation or break-symmetry and locomote to safety against thermal stresses. We show that the persistent blob locomotion emerges as a consequence of physical entanglement and functional differentiation of individuals based on spatial location within a blob. We validate these principles in robophysical swarming blobs, that pave the way for new classes of mechanofunctional active matter systems and collective emergent robotics.
Differential risk for COVID-19 in the first wave of the disease (February-April 2020) among migrants from several areas of the world living in Alcorcón (Spain): A population-based cohort study
Authors: Guijarro Carlos , Pérez-Fernández Elia , González-Piñeiro Beatriz , Meléndez Victoria , Goyanes Maria José , Renilla Ma Esther , Casas Maria Luisa , Sastre Isabel , Velasco María ,   Alcorcon COVID Investigators.
Published: May 2020

Little is known regarding the relevance of racial / ethnic background on the risk of COVID-IO infection, particularly in Europe. We evaluated the risk for COVID-19 among migrants from different areas of the world within a context of universal free access to medical care. We conducted a population-based cohort analysis of the cumulative incidence of PCR-confirmed COVID-19 among adult residents at Alcorcón (Spain) in the first wave of the disease. The crude cumulative incidence among migrants (n=20419) was higher than among Spaniards (n=131599): 8.81 and 6.51 and per 1000 inhabitants respectively (p<0.001) but differed by world region of origin. By negative binomial regression, adjusted for age and sex, relative risks (RR) for COVID-19 were not significantly different from Spaniards for individuals from Europe, Asia or Northern Africa. In contrast, there was a marked increased risk for Sub-Saharan Africa (RR 3.66, 95% confidence interval (Cl) 42-9.41, p=0.007), Caribbean (RR6.35, 95% Cl 3.83-10.55, p<0.001) and Latin-America (RR6.92, 95% Cl 4.49-10.67, p <0.001). Migrants from these areas of the world may deserve a closer attention both for clinical and epidemiological reasons.
Association of the Covid-19 lockdown with smoking, drinking, and attempts to quit in England: an analysis of 2019-2020 data
Authors: Jackson Sarah E. , Garnett Claire , Shahab Lion , Oldham Melissa , Brown Jamie
Published: May 2020

Aim

To examine changes in smoking, drinking, and quitting/reduction behaviour following the Covid-19 lockdown in England.

Design/setting

Monthly cross-sectional surveys representative of the adult population in England, aggregated before (April 2019 through February 2020) versus after (April 2020) the lockdown.

Participants

20,558 adults (≥16y).

Measurements

The independent variable was the timing of the Covid-19 lockdown in England (before vs. after March 2020). Dependent variables were: prevalence of smoking and high-risk drinking; past-year cessation and quit attempts (among past-year smokers); past-year attempts to reduce alcohol consumption (among high-risk drinkers); and use of evidence-based (e.g., prescription medication/face-to-face behavioural support) and remote support (telephone support/websites/apps) for smoking cessation and alcohol reduction (among smokers/high-risk drinkers who made a quit/reduction attempt). Covariates included age, sex, social grade, region, and level of nicotine and alcohol dependence (as relevant).

Findings

The Covid-19 lockdown was not associated with a significant change in smoking prevalence (17.0% (after) vs. 15.9% (before), C)R=1.09[95%CI 0.95-1.24]), but was associated with increases in the rate of quit attempts (39.6% vs. 29.1%, ORadj=1.56[l.23-1.98]) and cessation (8.8% vs. 4.1%, ORadj=2.63[1.69-4.09]) among past-year smokers. Among smokers who tried to quit, there was no significant change in use of evidence-based support (50.0% vs. 51.5%, ORadj=1.10[0.72-1.68]) but use of remote support increased (10.9% vs. 2.7%, ORadj=3.59[1.56-8.23]). Lockdown was associated with increases in the prevalence of high-risk drinking (38.3% vs. 25.1%, OR=1.85[1.67-2.06]) but also alcohol reduction attempts by high-risk drinkers (28.5% vs. 15.3%, ORadr2.16[1.77-2.64]). Among high-risk drinkers who made a reduction attempt, use of evidence-based support decreased (1.2% vs. 4.0%, ORadj=0.23[0.05-0.97]) and there was no significant change in use of remote support (6.9% vs. 6.1%, ORadj=1.32[0.64-2.75]).

Conclusions

In England, prevalence of high-risk drinking but not smoking has increased since the Covid-19 lockdown. Smokers and high-risk drinkers are more likely than before lockdown to report trying to quit smoking or reduce their alcohol consumption, and rates of smoking cessation are higher. Smokers are no less likely than before lockdown to use cessation support, with increased uptake of remote support. However, use of evidence-based support for alcohol reduction by high-risk drinkers has decreased, with no compensatory increase in use of remote support.
A chest radiography-based artificial intelligence deep-learning model to predict severe Covid-19 patient outcomes: the CAPE (Covid-19 AI Predictive Engine) Model
Authors: Liew Charlene , Quah Jessica , Goh Han Leong , Venkataraman Narayan
Published: May 2020

Background

Chest radiography may be used together with deep-learning models to prognosticate COVID-19 patient outcomes

Purpose

T o evaluate the performance of a deep-learning model for the prediction of severe patient outcomes from COVID-19 pneumonia on chest radiographs.

Methods

A deep-learning model (CAPE: Covid-19 AI Predictive Engine) was trained on 2337 CXR images including 2103 used only for validation while training. The prospective test set consisted of CXR images (n=70) obtained from RT-PCR confirmed COVID-19 pneumonia patients between 1 January and 30 April 2020 in a single center. The radiographs were analyzed by the AI model. Model performance was obtained by receiver operating characteristic curve analysis.

Results

In the prospective test set, the mean age of the patients was 46 (+/-16.2) years (84.2% male). The deep-learning model accurately predicted outcomes of ICU admission/mortality from COVID-19 pneumonia with an AUC of 0.79 (95% CI 0.79-0.96). Compared to traditional risk scoring systems for pneumonia based upon laboratory and clinical parameters, the model matched the EWS and MulBTSA risk scoring systems and outperformed CURB-65.

Conclusions

A deep-learning model was able to predict severe patient outcomes (ICU admission and mortality) from COVID-19 on chest radiographs.

Key Results

A deep-learning model was able to predict severe patient outcomes (ICU admission and mortality) from COVID-19 from chest radiographs with an AUC of 0.79, which is comparable to traditional risk scoring systems for pneumonia.

Summary Statement

This is a chest radiography-based AI model to prognosticate the risk of severe COVID-19 pneumonia outcomes.
Rala and the exocyst control Pvr trafficking and signaling to ensure lymph gland homeostasis inDrosophila melanogaster
Authors: Knævelsrud Helene , Baril Caroline , Gavory Gwenaëlle , Enserink Jorrit M. , Therrien Marc
Published: May 2020

The balance between hematopoietic progenitors and differentiated hemocytes is finely tuned during development. In the larval hematopoietic organ ofDrosophila, called the lymph gland, the receptor tyrosine kinase Pvr signals from differentiated cells to maintain a pool of undifferentiated progenitors. However, little is known about the processes that support Pvr function. The small GTPase Ral is involved in the regulation of several membrane trafficking events.Drosophilahas a single Ral protein, Rala, which has been implicated in the development of various tissues. Here, we investigated the involvement of Rala in the larval fly hematopoietic system. We discovered that the loss ofRalaactivity phenocopiesPvrloss of function by promoting hemocyte progenitor differentiation. Moreover, using epistasis analysis, we found that the guanine exchange factor RalGPS lies upstream of Rala in this event, whereas the exocyst and Rab11 are acting downstream. Strikingly, the loss of Rala activity leads to a considerable accumulation of Pvr at the plasma membrane, hence suggesting a trafficking defect and reduced Pvr function. Consistent with this hypothesis,Ralaloss of function phenotype in the lymph gland is fully suppressed by constitutive STAT activity, which normally mediates Pvr function in the lymph gland. Together, our findings unravel a novel RalGPS-Rala-exocyst-Rab11 axis for the maintenance of lymph gland homeostasis through Pvr.